rs142159132

Positions:

• chr4-113264911-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000357077.9(ANK2):​c.1401A>G​(p.Ala467=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,565,198 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: ANK2 ENST00000357077.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.04

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=-0.8).
• BP6: Variant 4-113264911-A-G is Benign according to our data. Variant chr4-113264911-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 238570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113264911-A-G is described in Lovd as [Benign]. Variant chr4-113264911-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00265 (404/152310) while in subpopulation NFE AF= 0.00418 (284/68016). AF 95% confidence interval is 0.00378. There are 0 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6	c.1401A>G	p.Ala467=	synonymous_variant	14/46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.1401A>G	p.Ala467=	synonymous_variant	14/46	1	NM_001148.6	ENSP00000349588	A2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00245 AC: 433 AN: 176464 Hom.: 1 AF XY: 0.00228 AC XY: 213 AN XY: 93352

Gnomad AFR exome AF: 0.000467

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00803

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000631

Gnomad FIN exome AF: 0.000247

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00334 AC: 4721 AN: 1412888 Hom.: 8 Cov.: 31 AF XY: 0.00333 AC XY: 2323 AN XY: 697980

Gnomad4 AFR exome AF: 0.000707

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00888

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000450

Gnomad4 FIN exome AF: 0.000219

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74480

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00366 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ANK2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2017	Variant summary: The ANK2 c.1401A>G (p.Ala467Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of ESE sites. These predictions have not been confirmed by functional studies. This variant was found in 99/23776 control chromosomes (including one homozygote) at a frequency of 0.0041639, which is approximately 416 times the estimated maximal expected allele frequency of a pathogenic ANK2 variant (0.00001), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory has classified this variant as benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiac arrhythmia, ankyrin-B-related Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 04, 2016	- -

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+	-	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 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	-0.80
CADD	Benign	3.2
DANN	Benign	0.48

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: rs142159132; hg19: chr4-114186067; COSMIC: COSV52192220;