4-113336045-C-T

Variant names:

• chr4-113336045-C-T
• rs3736575
• NM_001148.6:c.3579C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.97

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]

ACMG classification

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 rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.3579C>T	p.Arg1193Arg	synonymous_variant	Exon 30 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.3579C>T	p.Arg1193Arg	synonymous_variant	Exon 30 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34420 AN: 151914 Hom.: 6943 Cov.: 32

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

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.: 32 AF XY: 0.113 AC XY: 82132 AN XY: 726986

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.: 32 AF XY: 0.222 AC XY: 16486 AN XY: 74306

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

Submissions by phenotype

not specified Benign:2

Jul 10, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia, ankyrin-B-related Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jun 26, 2015

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. -

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

Other links and lift over

dbSNP: rs3736575; hg19: chr4-114257201; COSMIC: COSV52190796; COSMIC: COSV52190796;