4-113373380-C-T

Variant summary

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

The NM_001148.6(ANK2):c.11790C>T(p.Ile3930=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,614,106 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (37 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.43

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=-0.5).
• BP6: Variant 4-113373380-C-T is Benign according to our data. Variant chr4-113373380-C-T is described in ClinVar as [Benign]. Clinvar id is 136398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113373380-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00899 (1369/152244) while in subpopulation AFR AF= 0.0278 (1153/41536). AF 95% confidence interval is 0.0264. There are 18 homozygotes in gnomad4. There are 655 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.11790C>T	p.Ile3930=	synonymous_variant	45/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.11790C>T	p.Ile3930=	synonymous_variant	45/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152126 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00392 AC: 985 AN: 251186 Hom.: 11 AF XY: 0.00316 AC XY: 429 AN XY: 135750

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00185 AC: 2704 AN: 1461862 Hom.: 37 Cov.: 33 AF XY: 0.00174 AC XY: 1269 AN XY: 727236

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152244 Hom.: 18 Cov.: 33 AF XY: 0.00880 AC XY: 655 AN XY: 74440

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00644 Hom.: 8

Bravo AF: 0.0102

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2012	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. -
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	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 17, 2020

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 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	-0.50
Cadd	Benign	5.7
Dann	Benign	0.68

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: rs45517840; hg19: chr4-114294536;