rs373261456

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The NM_001148.6(ANK2):c.2969G>A(p.Arg990Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,068 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R990R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 10.0

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:

ANK2 (HGNC:):

ANK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

BS2

High AC in GnomAdExome4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.2969G>A	p.Arg990Gln	missense_variant	27/46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.2969G>A	p.Arg990Gln	missense_variant	27/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251298

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135820

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	Observed in an individual with a prolonged QTc interval and history of cardiac arrest due to ventricular fibrillation (PMID: 25632041); Observed in an patient with hypertrophic cardiomyopathy (PMID: 25351510) and a patient with LVNC and congenital heart disease in published literature (PMID: 32183154); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that the p.(R990Q) variant resulted in protein product with decreased spectrin-binding potential as well as improper localization and targeting (PMID: 25632041); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25632042, 32164423, 28191889, 33004838, 32183154, 25632041, 25351510) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 31, 2022	- -

Cardiac arrhythmia, ankyrin-B-related

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Feb 06, 2024	- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 990 of the ANK2 protein (p.Arg990Gln). This variant is present in population databases (rs373261456, gnomAD 0.004%). This missense change has been observed in individual(s) with prolonged QT interval and a history of sudden cardiac arrest, hypertrophic cardiomyopathy, and autism spectrum disorder (PMID: 25351510, 25632041, 28191889). ClinVar contains an entry for this variant (Variation ID: 190560). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANK2 protein function. Experimental studies have shown that this missense change affects ANK2 function (PMID: 25632041). 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The p.R990Q variant (also known as c.2969G>A), located in coding exon 27 of the ANK2 gene, results from a G to A substitution at nucleotide position 2969. The arginine at codon 990 is replaced by glutamine, an amino acid with highly similar properties. This variant co-occurred with a variant in the CUL7 gene in an individual from a cohort with autism spectrum/neurodevelopmental disorders (Stessman HA. Nat Genet. 2017 Apr;49(4):515-5260). This variant has been reported in an individual with prolonged QT interval, ventricular fibrillation, and sudden cardiac arrest, and in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Smith SA et al. Circulation, 2015 Feb;131:695-708; Lopes LR et al. Heart, 2015 Feb;101:294-301). In in vitro functional studies, this alteration appears to cause decreased spectrin binding with improper localization and targeting of membrane proteins (Smith SA et al. Circulation, 2015 Feb;131:695-708). According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, the association of this alteration with ANK2-related neurodevelopmental disorder is unknown; however, the association with ANK2-related arrhythmia is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.88

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

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

.;.;.;.;M;M;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D;D;.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;.;D

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0, 1.0

.;.;D;.;D;D;.;.;D

Vest4

0.94, 0.92, 0.86, 0.90, 0.96

MVP

0.78

MPC

1.6

ClinPred

0.93

GERP RS

5.9

Varity_R

0.57

gMVP

0.80

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