chr4-113365051-T-A

Position:

chr4-113365051-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001148.6(ANK2):c.10901T>A(p.Val3634Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,852 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 22 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8O:1

Conservation

PhyloP100: 3.50

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 -12 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=0.01469788).

BP6

Variant 4-113365051-T-A is Benign according to our data. Variant chr4-113365051-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67599.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, not_provided=1, Uncertain_significance=2}. Variant chr4-113365051-T-A is described in Lovd as [Benign]. Variant chr4-113365051-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00206 (314/152274) while in subpopulation AMR AF= 0.00464 (71/15290). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.10901T>A	p.Val3634Asp	missense_variant	41/46	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.10901T>A	p.Val3634Asp	missense_variant	41/46	1	NM_001148.6	ENSP00000349588	A2	Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.00205

AC:

312

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00245

AC:

615

AN:

251264

Hom.:

AF XY:

0.00256

AC XY:

348

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00209

AC:

3057

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1610

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000626

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00206

AC:

314

AN:

152274

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00266

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00196

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00273

AC:

332

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	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: 31920912, 32164423, 24025405, 17242276, 27884173, 23631430, 23174487) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANK2: PM5, BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	- -

Cardiac arrhythmia

Benign:1Other: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 Cardiac arrhythmia in the following publications (PMID:17242276). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

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

Nov 18, 2019

- -

Cardiac arrhythmia, ankyrin-B-related

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ANK2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

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). -

Familial dilated cardiomyopathy and peripheral neuropathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 03, 2019

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.14

Eigen_PC

Benign

0.022

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.015

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

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.2

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

MutationTaster

Benign

1.0

D;D;D;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.8

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

REVEL

Uncertain

0.61

Sift

Benign

0.36

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

Sift4G

Benign

0.28

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

Polyphen

0.039

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

Vest4

0.69

MVP

0.98

MPC

0.16

ClinPred

0.028

GERP RS

4.3

Varity_R

0.14

gMVP

0.72

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