rs29341

chr4-113292475-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001148.6(ANK2):c.2337C>T(p.Val779=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,611,660 control chromosomes in the GnomAD database, including 1,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (96 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1064 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.922

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-113292475-C-T is Benign according to our data. Variant chr4-113292475-C-T is described in ClinVar as [Benign]. Clinvar id is 263475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113292475-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.922 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0336 (5125/152352) while in subpopulation NFE AF= 0.0383 (2606/68038). AF 95% confidence interval is 0.0371. There are 96 homozygotes in gnomad4. There are 2563 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 5122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.2337C>T	p.Val779=	synonymous_variant	21/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.2337C>T	p.Val779=	synonymous_variant	21/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5122 AN: 152234 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0289 AC: 7068 AN: 244874 Hom.: 148 AF XY: 0.0291 AC XY: 3851 AN XY: 132402

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0353 AC: 51477 AN: 1459308 Hom.: 1064 Cov.: 32 AF XY: 0.0350 AC XY: 25434 AN XY: 725674

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0589

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0305

GnomAD4 genome AF: 0.0336 AC: 5125 AN: 152352 Hom.: 96 Cov.: 32 AF XY: 0.0344 AC XY: 2563 AN XY: 74506

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.0316

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0559

Gnomad4 NFE AF: 0.0383

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0344 Hom.: 75

Bravo AF: 0.0309

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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	-0.45
Cadd	Benign	9.0
Dann	Benign	0.90

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: rs29341; hg19: chr4-114213631;