rs142612379

Variant names:

• chr4-113360844-G-A
• rs142612379
• NM_001148.6:c.10703G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001148.6(ANK2):​c.10703G>A​(p.Arg3568Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000515 in 1,612,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3568W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.33
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.148776).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000204 (31/152208) while in subpopulation AFR AF = 0.000626 (26/41524). AF 95% confidence interval is 0.000439. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 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.10703G>A	p.Arg3568Gln	missense	Exon 39 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.10844G>A	p.Arg3615Gln	missense	Exon 41 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.10820G>A	p.Arg3607Gln	missense	Exon 40 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.10703G>A	p.Arg3568Gln	missense	Exon 39 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.10844G>A	p.Arg3615Gln	missense	Exon 41 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4448G>A	p.Arg1483Gln	missense	Exon 38 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000520 AC: 13 AN: 250134 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1460532 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726582

African (AFR) AF: 0.000209 AC: 7 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39610

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111278

Other (OTH) AF: 0.000166 AC: 10 AN: 60298

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74420

African (AFR) AF: 0.000626 AC: 26 AN: 41524

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiac arrhythmia, ankyrin-B-related (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.55
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.50	P
Vest4		0.26
MVP		0.77
MPC		0.12
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.24
gMVP		0.37
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142612379; hg19: chr4-114282000; COSMIC: COSV52145945;