4-113355724-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001148.6(ANK2):c.7106T>C(p.Val2369Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,532 control chromosomes in the GnomAD database, including 10,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2369G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1310 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8810 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0710

Publications

26 publications found

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 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

ANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010992885).

BP6

Variant 4-113355724-T-C is Benign according to our data. Variant chr4-113355724-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6 link	c.7106T>C	p.Val2369Ala	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.7106T>C	p.Val2369Ala	missense_variant	Exon 38 of 46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18656

AN:

151688

Hom.:

1308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.0276

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.0945

AC:

23702

AN:

250714

AF XY:

0.0935

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.0635

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.105

AC:

154195

AN:

1461726

Hom.:

8810

Cov.:

AF XY:

0.104

AC XY:

75891

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.185

AC:

6195

AN:

33468

American (AMR)

AF:

0.0670

AC:

2994

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3118

AN:

26124

East Asian (EAS)

AF:

0.000302

AC:

AN:

39690

South Asian (SAS)

AF:

0.0365

AC:

3150

AN:

86256

European-Finnish (FIN)

AF:

0.107

AC:

5715

AN:

53406

Middle Eastern (MID)

AF:

0.164

AC:

948

AN:

5764

European-Non Finnish (NFE)

AF:

0.113

AC:

125528

AN:

1111916

Other (OTH)

AF:

0.108

AC:

6535

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

8435

16870

25306

33741

42176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4394

8788

13182

17576

21970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.123

AC:

18677

AN:

151806

Hom.:

1310

Cov.:

AF XY:

0.120

AC XY:

8882

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.175

AC:

7238

AN:

41402

American (AMR)

AF:

0.0937

AC:

1428

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

388

AN:

3466

East Asian (EAS)

AF:

0.000776

AC:

AN:

5156

South Asian (SAS)

AF:

0.0278

AC:

133

AN:

4784

European-Finnish (FIN)

AF:

0.100

AC:

1059

AN:

10556

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8049

AN:

67884

Other (OTH)

AF:

0.130

AC:

273

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

830

1660

2491

3321

4151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.117

Hom.:

3443

Bravo

AF:

0.127

TwinsUK

AF:

0.121

AC:

448

ALSPAC

AF:

0.106

AC:

409

ESP6500AA

AF:

0.186

AC:

819

ESP6500EA

AF:

0.116

AC:

1000

ExAC

AF:

0.0981

AC:

11905

Asia WGS

AF:

0.0290

AC:

103

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30564305) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiac arrhythmia, ankyrin-B-related

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 23, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Benign:1

Aug 18, 2011

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

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

0.069

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.59

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.10

T;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.6

N;.

PhyloP100

0.071

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.055

Sift

Benign

0.57

T;T

Sift4G

Benign

0.78

T;T

Vest4

0.036

MPC

0.094

ClinPred

0.0012

GERP RS

0.026

Varity_R

0.019

gMVP

0.026

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over