NM_001148.6:c.6632C>T

Variant names:

• chr4-113355250-C-T
• rs567825537
• NM_001148.6:c.6632C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001148.6(ANK2):​c.6632C>T​(p.Ala2211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2211A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]

ANK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11087373).
• BP6: Variant 4-113355250-C-T is Benign according to our data. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355. Variant chr4-113355250-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 581355.
• BS2: High AC in GnomAdExome4 at 39 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.6632C>T	p.Ala2211Val	missense_variant	Exon 38 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.6632C>T	p.Ala2211Val	missense_variant	Exon 38 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250366 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461792 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111946

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2211 of the ANK2 protein (p.Ala2211Val). This variant is present in population databases (rs567825537, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 581355). -

Cardiac arrhythmia, ankyrin-B-related Uncertain:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 06, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.3
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.080
Sift	Benign	0.061	T;T
Sift4G	Benign	0.64	T;T
Vest4		0.059
MVP		0.30
MPC		0.080
ClinPred		0.058	T
GERP RS		2.9
Varity_R		0.046
gMVP		0.14
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs567825537; hg19: chr4-114276406;