rs33966911

chr4-113354087-C-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.5469C>T(p.Pro1823=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0959 in 1,613,984 control chromosomes in the GnomAD database, including 8,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (610 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7677 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.10

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=-0.69).
• BP6: Variant 4-113354087-C-T is Benign according to our data. Variant chr4-113354087-C-T is described in ClinVar as [Benign]. Clinvar id is 257580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113354087-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.5469C>T	p.Pro1823=	synonymous_variant	38/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.5469C>T	p.Pro1823=	synonymous_variant	38/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11493 AN: 152074 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0793 AC: 19894 AN: 251024 Hom.: 1063 AF XY: 0.0816 AC XY: 11068 AN XY: 135642

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0301

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0980 AC: 143328 AN: 1461792 Hom.: 7677 Cov.: 34 AF XY: 0.0973 AC XY: 70767 AN XY: 727190

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.0567

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0307

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.0937

GnomAD4 genome AF: 0.0755 AC: 11484 AN: 152192 Hom.: 610 Cov.: 32 AF XY: 0.0729 AC XY: 5420 AN XY: 74396

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.0688

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0231

Gnomad4 FIN AF: 0.0972

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.0981

Alfa AF: 0.100 Hom.: 444

Bravo AF: 0.0718

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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 12, 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	-0.69
Cadd	Benign	0.99
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: rs33966911; hg19: chr4-114275243;