rs29372
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2
The ENST00000357077.9(ANK2):āc.2060A>Gā(p.Asn687Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000357077.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.2060A>G | p.Asn687Ser | missense_variant | 18/46 | ENST00000357077.9 | NP_001139.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.2060A>G | p.Asn687Ser | missense_variant | 18/46 | 1 | NM_001148.6 | ENSP00000349588 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251100Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135690
GnomAD4 exome AF: 0.000233 AC: 341AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160AN XY: 727152
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2023 | Identified in a cohort of stillbirths undergoing sequencing for genes associated with arrhythmia; however, clinical information is not available (Munroe et al., 2018); 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: 25649125, 27527004, 16741161, 23861362, 17161064, 19862833, 29874177) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | ANK2: BP4 - |
not specified Benign:2
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2023 | Variant summary: ANK2 c.2060A>G (p.Asn687Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 283602 control chromosomes (gnomAD). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is benign. c.2060A>G has been reported in the literature in one individual affected with torsades de pointes and one stillbirth case (Mank-Seymour_2006, Munroe_2018). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 14, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 687 of the ANK2 protein (p.Asn687Ser). This variant is present in population databases (rs29372, gnomAD 0.01%). This missense change has been observed in individual(s) with unexplained stillbirth (PMID: 29874177). ClinVar contains an entry for this variant (Variation ID: 190594). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiac arrhythmia, ankyrin-B-related Uncertain:1
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Dec 10, 2015 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at