4-113369688-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001148.6(ANK2):c.11493G>T(p.Glu3831Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.106

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051511526).

BP6

Variant 4-113369688-G-T is Benign according to our data. Variant chr4-113369688-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 190533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00065 (99/152262) while in subpopulation AFR AF= 0.00236 (98/41560). AF 95% confidence interval is 0.00198. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6 link	c.11493G>T	p.Glu3831Asp	missense_variant	Exon 43 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.11493G>T	p.Glu3831Asp	missense_variant	Exon 43 of 46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

250912

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000650

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ANK2-related disorder

Benign:1

Jun 10, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Apr 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25351510) -

Long QT syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 14, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiac arrhythmia, ankyrin-B-related

Benign:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.4

DANN

Benign

0.83

DEOGEN2

Benign

0.31

.;.;T;T;T;.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0052

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

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

1.6

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.82

N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.020

D;D;T;T;T;T;T

Sift4G

Benign

0.20

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

Polyphen

0.015

B;P;.;.;P;.;.

Vest4

0.12

MutPred

0.43

.;.;.;.;Gain of glycosylation at S924 (P = 0.0082);.;.;

MVP

0.68

MPC

0.084

ClinPred

0.014

GERP RS

2.7

Varity_R

0.037

gMVP

0.14

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