Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001148.6(ANK2):c.10901T>A(p.Val3634Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,852 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3634I) has been classified as Uncertain significance.
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]
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, ANK2
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.01469788).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-113365051-T-A is Benign according to our data. Variant chr4-113365051-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67599.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2, Benign=1, not_provided=1}. Variant chr4-113365051-T-A is described in Lovd as [Benign]. Variant chr4-113365051-T-A is described in Lovd as [Likely_benign].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00206 (314/152274) while in subpopulation AMR AF= 0.00464 (71/15290). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 22, 2021
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31920912, 32164423, 24025405, 17242276, 27884173, 23631430, 23174487) -
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 27, 2017
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jul 01, 2024
ANK2: PM5, BP4, BS2 -
Cardiac arrhythmia Benign:1Other:1
Likely benign, criteria provided, single submitter
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jun 24, 2013
- -
not provided, no classification provided
literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
-
This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:17242276). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Conduction disorder of the heart Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Nov 18, 2019
- -
Cardiac arrhythmia, ankyrin-B-related Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
ANK2-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
May 30, 2019
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Familial dilated cardiomyopathy and peripheral neuropathy Benign:1
Benign, criteria provided, single submitter
clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Jun 03, 2019
- -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 22, 2024
- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 14, 2018
This alteration is classified as likely 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. -