4-113336037-C-T

Variant names:

• chr4-113336037-C-T
• rs771751897
• NM_001148.6:c.3571C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001148.6(ANK2):​c.3571C>T​(p.Arg1191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1191Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.462
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001148.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.3571C>T	p.Arg1191Trp	missense	Exon 30 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.3712C>T	p.Arg1238Trp	missense	Exon 32 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.3688C>T	p.Arg1230Trp	missense	Exon 31 of 50	NP_001373104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.3571C>T	p.Arg1191Trp	missense	Exon 30 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.3712C>T	p.Arg1238Trp	missense	Exon 32 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.3571C>T	p.Arg1191Trp	missense	Exon 30 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249980 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiac arrhythmia, ankyrin-B-related (1)
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.46
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.80
MPC		1.6
ClinPred		0.86	D
GERP RS		1.0
Varity_R		0.65
gMVP		0.58
Mutation Taster		=23/77	disease causing

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: rs771751897; hg19: chr4-114257193; COSMIC: COSV52150472; COSMIC: COSV52150472;