rs3796928

Positions:

chr4-113354786-C-G

Variant summary

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

The ENST00000357077.9(ANK2):c.6168C>G(p.Leu2056=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,864 control chromosomes in the GnomAD database, including 4,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2082 hom., cov: 32)

Exomes 𝑓: 0.032 ( 2327 hom. )

Consequence

ANK2
ENST00000357077.9 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0800

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 4-113354786-C-G is Benign according to our data. Variant chr4-113354786-C-G is described in ClinVar as [Benign]. Clinvar id is 257581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113354786-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 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.6168C>G	p.Leu2056=	synonymous_variant	38/46	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.6168C>G	p.Leu2056=	synonymous_variant	38/46	1	NM_001148.6	ENSP00000349588	A2	Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16018

AN:

152022

Hom.:

2079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0561

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.0512

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0929

GnomAD3 exomes

AF:

0.0444

AC:

11128

AN:

250746

Hom.:

893

AF XY:

0.0392

AC XY:

5311

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.315

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.0519

Gnomad SAS exome

AF:

0.0228

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0240

Gnomad OTH exome

AF:

0.0371

GnomAD4 exome

AF:

0.0317

AC:

46319

AN:

1461724

Hom.:

2327

Cov.:

AF XY:

0.0307

AC XY:

22333

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.314

Gnomad4 AMR exome

AF:

0.0314

Gnomad4 ASJ exome

AF:

0.0230

Gnomad4 EAS exome

AF:

0.0563

Gnomad4 SAS exome

AF:

0.0236

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.0231

Gnomad4 OTH exome

AF:

0.0479

GnomAD4 genome

AF:

0.105

AC:

16044

AN:

152140

Hom.:

2082

Cov.:

AF XY:

0.102

AC XY:

7586

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.310

Gnomad4 AMR

AF:

0.0560

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.0511

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0113

Gnomad4 NFE

AF:

0.0232

Gnomad4 OTH

AF:

0.0915

Alfa

AF:

0.0444

Hom.:

178

Bravo

AF:

0.117

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0257

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiac arrhythmia, ankyrin-B-related

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

-0.83

CADD

Benign

0.40

DANN

Benign

0.26

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