4-113357121-C-T

Position:

chr4-113357121-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001148.6(ANK2):c.8503C>T(p.Pro2835Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,613,944 control chromosomes in the GnomAD database, including 7,897 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2963 hom., cov: 32)

Exomes 𝑓: 0.058 ( 4934 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.391

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 Benign. Variant got -19 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=0.0031706393).

BP6

Variant 4-113357121-C-T is Benign according to our data. Variant chr4-113357121-C-T is described in ClinVar as [Benign]. Clinvar id is 191560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113357121-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.8503C>T	p.Pro2835Ser	missense_variant	38/46	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.8503C>T	p.Pro2835Ser	missense_variant	38/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21187

AN:

152024

Hom.:

2951

Cov.:

show subpopulations

Gnomad AFR

AF:

0.361

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0398

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.0865

AC:

21704

AN:

250950

Hom.:

1827

AF XY:

0.0810

AC XY:

10990

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.368

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.0821

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0408

Gnomad OTH exome

AF:

0.0805

GnomAD4 exome

AF:

0.0580

AC:

84795

AN:

1461802

Hom.:

4934

Cov.:

AF XY:

0.0585

AC XY:

42522

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.370

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.0858

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0210

Gnomad4 NFE exome

AF:

0.0397

Gnomad4 OTH exome

AF:

0.0803

GnomAD4 genome

AF:

0.140

AC:

21236

AN:

152142

Hom.:

2963

Cov.:

AF XY:

0.137

AC XY:

10224

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.362

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.0818

Gnomad4 EAS

AF:

0.116

Gnomad4 SAS

AF:

0.107

Gnomad4 FIN

AF:

0.0209

Gnomad4 NFE

AF:

0.0398

Gnomad4 OTH

AF:

0.126

Alfa

AF:

0.0639

Hom.:

1654

Bravo

AF:

0.156

TwinsUK

AF:

0.0421

AC:

156

ALSPAC

AF:

0.0428

AC:

165

ESP6500AA

AF:

0.342

AC:

1509

ESP6500EA

AF:

0.0457

AC:

393

ExAC

AF:

0.0900

AC:

10931

Asia WGS

AF:

0.123

AC:

427

AN:

3478

EpiCase

AF:

0.0443

EpiControl

AF:

0.0421

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22100668) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 18, 2016	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiac arrhythmia, ankyrin-B-related

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.57

DANN

Benign

0.88

DEOGEN2

Benign

0.28

T;T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

L;.;.

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.37

N;N;.

REVEL

Benign

0.037

Sift

Benign

0.56

T;T;.

Sift4G

Benign

0.89

T;T;D

Vest4

0.046

MPC

0.080

ClinPred

0.00017

GERP RS

2.5

Varity_R

0.015

gMVP

0.043

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