chr4-113348277-A-G

Position:

chr4-113348277-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001148.6(ANK2):c.4373A>G(p.Glu1458Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

ANK2
NM_001148.6 missense, splice_region

Scores

Splicing: ADA: 0.7324

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 9.04

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK2. . Gene score misZ 1.9641 (greater than the threshold 3.09). Trascript score misZ 4.2513 (greater than threshold 3.09). GenCC has associacion of gene with heart conduction disease, Brugada syndrome, long QT syndrome, complex neurodevelopmental disorder, cardiac arrhythmia, ankyrin-B-related, catecholaminergic polymorphic ventricular tachycardia.

BP4

Computational evidence support a benign effect (MetaRNN=0.01375708).

BS2

High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.4373A>G	p.Glu1458Gly	missense_variant, splice_region_variant	36/46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.4373A>G	p.Glu1458Gly	missense_variant, splice_region_variant	36/46	1	NM_001148.6	ENSP00000349588	A2	Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

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:

0.000941

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000546

AC:

137

AN:

251086

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000735

AC:

1074

AN:

1461172

Hom.:

Cov.:

AF XY:

0.000718

AC XY:

522

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000850

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152230

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000737

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related

Pathogenic:2Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 22, 2014	The p.Glu1458Gly variant (also referred to as p.Glu1425Gly) has been identified in >20 affected members of a large kindred with autosomal dominant long QT syndrome (Mohler 2003). It has been identified in an unaffected individual whose three siblings died suddenly at a young age (Mohler 2004). It has also been identified in 0.06% (41/67458) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72544141). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008). In p.Glu1458Gly variant is likely pathogenic. -
Pathogenic, flagged submission	literature only	OMIM	Jun 15, 2004	- -
Uncertain significance, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 16, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2024	Reported in several individuals with sudden death/SIDS (PMID: 26350513, 27930701, 29247119, 28074886) and in association with HCM (PMID: 23396983, 25351510), although additional cardiogenetic variants were identified in some of these probands; Reported in several individuals without a known history of cardiovascular disease (PMID: 23861362, 26159999, 28654958, 29431110); Identified as secondary finding in a cohort of patients with intellectual disability or developmental delay referred for WES/WGS who was reported to have a clinical diagnosis of HCM and arrhythmia (PMID: 29790872); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated this variant results in abnormal Ca2+ signaling in mouse cardiomyocytes, and mice heterozygous for this variant had a high incidence of sudden death after exercise and exposure to epinephrine (PMID: 12571597, 17242276); This variant is associated with the following publications: (PMID: 17242276, 23396983, 26159999, 15178757, 7485162, 29247119, 28880023, 27930701, 28654958, 28074886, 18832177, 26220970, 26350513, 19394342, 29431110, 20724725, 22581653, 28988457, 25351510, 32164423, 29198934, 35990955, 12571597, 29790872, 23861362) -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2018	The ANK2 c.4373A>G; p.Glu1458Gly variant (rs72544141), also known as p.Glu1425Gly, is reported in the literature in individuals affected with Long QT syndrome, sinus node dysfunction, arrhythmia, sudden unexplained death, and hypertrophic cardiomyopathy (Hertz 2016, Le Scouarnec 2008, Lin 2017. Lopes 2013, Mohler 2003, Neubauer 2017). In one large family, this variant segregated with long QT syndrome and sinus node dysfunction in more than 20 affected individuals and was not observed in any unaffected individuals (Le Scouarnec 2008, Mohler 2003). However, this variant was also observed in a healthy individual with normal QT interval (Mohler 2004), and it was not significantly associated with longer QT interval in a large Dutch cohort (Ghouse 2015). Further, the p.Glu1458Gly variant is found in the Latino population with an overall allele frequency of 0.11% (38/24226 alleles, including one homozygote) in the Genome Aggregation Database, and this population frequency exceeds the estimated prevalence of Long QT syndrome at 1 in 2000 (Lin 2017). In mouse cardiomyocytes lacking one copy of ANK2, transfection of the p.Glu1458Gly variant fails to rescue decreased spontaneous contraction rate to the same extent as wildtype protein (Mohler 2003, Mohler 2007). The glutamate at codon 1458 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Glu1458Gly variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hertz CL et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet. 2016 Jun;24(6):817-22. Le Scouarnec S et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15617-22. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6). Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Mohler PJ et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Mohler PJ et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. Mohler PJ et al. Defining the cellular phenotype of ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007 Jan 30;115(4):432-41. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. " -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2024	- -

Long QT syndrome

Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

Long QT syndrome 4

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Jun 15, 2004

- -

Conduction disorder of the heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2021

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. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12571597;PMID:15178757;PMID:18832177). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;T;.;D;T;T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

.;.;.;L;L;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D;D;N

REVEL

Uncertain

0.31

Sift

Benign

0.35

T;T;T;T;T;T;T;T

Sift4G

Benign

0.42

T;T;T;T;T;T;T;T

Polyphen

0.012, 0.016, 0.0010

.;B;.;B;.;.;B;.

Vest4

0.55, 0.44, 0.49, 0.40, 0.46, 0.45

MVP

0.62

MPC

1.0

ClinPred

0.13

GERP RS

5.7

Varity_R

0.52

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over