4-113336045-C-T

Position:

chr4-113336045-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001148.6(ANK2):c.3579C>T(p.Arg1193Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,414 control chromosomes in the GnomAD database, including 20,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 6971 hom., cov: 32)

Exomes 𝑓: 0.11 ( 13541 hom. )

Consequence

ANK2
NM_001148.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.97

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 4-113336045-C-T is Benign according to our data. Variant chr4-113336045-C-T is described in ClinVar as [Benign]. Clinvar id is 136390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113336045-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.54 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.3579C>T	p.Arg1193Arg	synonymous_variant	30/46	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.3579C>T	p.Arg1193Arg	synonymous_variant	30/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34420

AN:

151914

Hom.:

6943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.545

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.0968

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0621

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.137

AC:

34303

AN:

249536

Hom.:

4046

AF XY:

0.129

AC XY:

17419

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.563

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.0990

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.0616

Gnomad NFE exome

AF:

0.0990

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.113

AC:

165864

AN:

1461382

Hom.:

13541

Cov.:

AF XY:

0.113

AC XY:

82132

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.567

Gnomad4 AMR exome

AF:

0.142

Gnomad4 ASJ exome

AF:

0.102

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.0658

Gnomad4 NFE exome

AF:

0.0980

Gnomad4 OTH exome

AF:

0.135

GnomAD4 genome

AF:

0.227

AC:

34501

AN:

152032

Hom.:

6971

Cov.:

AF XY:

0.222

AC XY:

16486

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.546

Gnomad4 AMR

AF:

0.157

Gnomad4 ASJ

AF:

0.0968

Gnomad4 EAS

AF:

0.117

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.0621

Gnomad4 NFE

AF:

0.101

Gnomad4 OTH

AF:

0.196

Alfa

AF:

0.133

Hom.:

2845

Bravo

AF:

0.249

Asia WGS

AF:

0.149

AC:

517

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.0988

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	Jan 13, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.65

DANN

Benign

0.83

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