rs780131495

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001148.6(ANK2):c.7517G>A(p.Arg2506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,948 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.31

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37661213).

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6 link	c.7517G>A	p.Arg2506Gln	missense_variant	Exon 38 of 46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 link	c.7517G>A	p.Arg2506Gln	missense_variant	Exon 38 of 46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000559

AC:

AN:

250578

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000697

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Located in exon 38, which is reported as being expressed in a brain-specific transcript (Otto et al, 1991; Cunha et al, 2008; Wu et al, 2015); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#406493; Landrum et al., 2016) -

Apr 05, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

We have seen this variant in an adult with familial atrial fibrillation in our center. Testing done by Invitae. p.Arg2506Gln (c.7517G>A) in exon 38 of the ANK2 gene (NM_001148.4) Chromosome position 4:114277291 G / A Given the lack of case data and the presence in gnomAD, with an elevated allele frequency in individuals of Ashkenazi Jewish descent, we consider this a variant of uncertain significance, probably benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). ANK2: The ANK2 gene encodes ankyrin-2 (aka ankyrin-B), which links integral membrane proteins to the underlying spectrin-actin cytoskeleton and plays a role in signaling and membrane protein trafficking and regulation. Mohler et al (2003) first proposed a link between ANK2 and long QT syndrome. A missense variant in ANK2 co-segregated with disease in 24 affected members of a large French kindred. They had a mixed phenotype of long QT syndrome, sinus node dysfunction and atrial fibrillation, which has been labeled long QT type 4. Inheritance was autosomal dominant. Sinus node dysfunction was detectable in utero while atrial fibrillation was only observed in adulthood. Mice heterozygous for a null variant in ANK2 were shown to be haploinsufficient for ankyrin-2 and to have arrhythmias similar to those seen in the human patients. In vitro studies revealed disruption of the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1, 4, 5- triphosphate receptors. Altered calcium signaling was also observed and was considered the rationale for arrhythmia. Additional cases of long QT and other arrhythmic phenotypes associated with ANK2 have since been reported (see Smith et al 2012 for review). Cunha et al (2011) provided a summary atrial fibrillation in families with ANK2 variants: "We identified a high incidence of AF in ANK2 mutation-positive probands. Probands harboring ANK2 loss-of-function alleles displayed early onset AF, commonly progressing to permanent AF.9, 13, 14 In one large kindred (74 members), 13 of 25 ANK2 loss-of-function variant carriers (phenotypes previously mapped to ANK2, Zmax=7.059) displayed AF (mean onset 40 Â±18 years, 5 paroxysmal, 8 permanent), whereas non-carriers were asymptomatic.Only two individuals were non-penetrant for atrial phenotypes. The others had AF, AF with sinus node dysfunction, or sinus node dysfunction alone. In an unrelated large family, 20/36 individuals were positive for the ANK2 disease allele (maximal LOD score was for marker D4S1616; linkage Zmax=5.9, ?=0), and 3 of 20 disease allele carriers displayed AF (mean onset 48 Â±12 years, two paroxysmal, 1 permanent), while thirteen displayed sinus node disease requiring pacemaker implantation (mean age for implantation 30Â±18 years12). Only four individuals were non-penetrant for atrial phenotypes." (see Cunha et al 2011 for cited references). Per the lab report and our searches, the variant has not been reported in association with disease to date. It is not present in ClinVar as of 4/4/2017. There are no other variants at or near this codon reported as pathogenic in ClinVar as of 4/4/2017. Per the Invitae lab report: "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably"; Align-GVGD: "Class C0")." This is a nonconservative amino acid change, from a positively-charged Arginine to a polar Glutamine. The Arginine at this location is conserved across all mammals, and across all other vertebrates we have information for except for fish, in which it varies widely. The variant was reported online in 15 of 138,135 individuals in the in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi -

Long QT syndrome

Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2506 of the ANK2 protein (p.Arg2506Gln). This variant is present in population databases (rs780131495, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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: 406493). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

-0.042

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.85

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.21

T;T

Vest4

0.47

MVP

0.75

MPC

0.48

ClinPred

0.39

GERP RS

6.0

Varity_R

0.29

gMVP

0.079

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

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