chr17-70175316-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2
The NM_000891.3(KCNJ2):c.277G>A(p.Val93Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V93A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.277G>A | p.Val93Ile | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.277G>A | p.Val93Ile | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.277G>A | p.Val93Ile | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251482Hom.: 1 AF XY: 0.000169 AC XY: 23AN XY: 135918
GnomAD4 exome AF: 0.000118 AC: 172AN: 1461894Hom.: 1 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 727248
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74468
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 9 Pathogenic:2Uncertain:1
Likely pathogenic, flagged submission | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Dec 17, 2021 | We observed p.V93I variant in a 15-y.o. female proband with borderline QTc prolongation. This variant was shown to have in vitro effect (PS3 criteria); several in silico tools predict the variant to be pathogenic (PP3 criteria); additionally, it was previously shown for the variant to have a gain-of-function effect of this variant on Kir2.1 channel. Based on the evidence, we consider the p.V93I variant to be likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 18, 2017 | The KCNJ2 c.277G>A (p.Val93Ile) variant has been reported one study in association with familial atrial fibrillation (AF) in which it is found in a heterozygous state in all five affected members of the same Chinese Han family; the proband, two siblings, father and niece (Xia et al. 2005). The proband had paroxysmal AF two to three times a month. His father and older sister were in permanent AF prior to death, his younger sister suffered from paroxysmal AF once or twice a week and his niece showed paroxysmal AF on a 24 hour ECG. All affected individuals were greater than 50 years of age at diagnosis. The variant was also found in a heterozygous state in two nephews, neither of whom showed paroxysmal AF on a 24 hour ECG, but who were 42 and 33 years of age at the time of study. The variant was not found in any other unaffected family members. The p.Val93Ile variant was also absent from 420 unrelated healthy Chinese individuals but is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Consortium. The p.Val931Ile variant is located in the outer helix of the M1 transmembrane domain of the protein which is a highly conserved region. Electrophysiological evaluation using whole-cell patch-clamping in COS-7 and HEK293 cells showed higher amplitude potentials compared to wildtype, demonstrating a gain of function effect of the variant on inward and outward KCNJ2 currents (Xia et al. 2005). Based on the evidence, the p.Val93Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial atrial fibrillation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, flagged submission | literature only | OMIM | Jul 15, 2005 | - - |
Atrial fibrillation Uncertain:1Other:1
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 Atrial fibrillation in the following publications (PMID:15922306;PMID:19041665). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the KCNJ2 protein (p.Val93Ile). This variant is present in population databases (rs147750704, gnomAD 0.03%). This missense change has been observed in individual(s) with atrial fibrillation and/or long QT syndrome (PMID: 15922306, 23631430, 25410959, 35456365). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30121). 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 KCNJ2 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ2 function (PMID: 15922306, 19041665, 19111761). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 23631430, 15922306, 19041665, 29247119, 25410959) - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PM1, BP4 - |
Andersen Tawil syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 19, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2022 | 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. - |
Short QT syndrome type 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 19, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at