chr4-113255880-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_001148.6(ANK2):c.1136G>T(p.Arg379Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R379C) has been classified as Likely benign.
Frequency
Consequence
NM_001148.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.1136G>T | p.Arg379Leu | missense_variant | 11/46 | ENST00000357077.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.1136G>T | p.Arg379Leu | missense_variant | 11/46 | 1 | NM_001148.6 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251300Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135800
GnomAD4 exome AF: 0.000233 AC: 340AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.000239 AC XY: 174AN XY: 727242
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74448
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 02, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 190592; Landrum et al., 2016) - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 379 of the ANK2 protein (p.Arg379Leu). This variant is present in population databases (rs186264035, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 190592). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANK2 protein function. 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 17, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2023 | 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