rs766143485
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_000891.3(KCNJ2):c.119G>A(p.Arg40Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,614,054 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40L) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.119G>A | p.Arg40Gln | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.119G>A | p.Arg40Gln | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.119G>A | p.Arg40Gln | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727246
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2018 | The R40Q variant of uncertain significance in the KCNJ2 gene has been reported as a likely benign variant in one patient with primary electrical disease who also harbors a loss of function variant in the PKP2 gene (Proost et al., 2017). This variant is observed in 6/277196 (0.002%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R40Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 08, 2022 | The KCNJ2 c.119G>A; p.Arg40Gln variant (rs766143485) is reported in the literature in an individual affected with fetal thrombotic vasculopathy (Munroe 2018), and an individual affected with primary electrical disease who also carried a pathogenic PKP2 variant (Proost 2017). This variant is also reported in ClinVar (Variation ID: 324830), but is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 40 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.201). In vitro functional analyses demonstrate reduced channel function (Munroe 2018). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Munroe PB et al. Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. Circ Genom Precis Med. 2018 Jan;11(1):e001817. PMID: 29874177. Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. PMID: 28341588. - |
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3;C3151431:Atrial fibrillation, familial, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 31, 2021 | - - |
SUDDEN INFANT DEATH SYNDROME Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Robert's Program, Boston Children's Hospital | Oct 01, 2021 | We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. - |
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the KCNJ2 protein (p.Arg40Gln). This variant is present in population databases (rs766143485, gnomAD 0.008%). This missense change has been observed in individual(s) with primary electrical disease (PED), however this individual also had a pathogenic variant in another PED-related gene (PMID: 28341588, 29874177). ClinVar contains an entry for this variant (Variation ID: 324830). 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 have shown that this missense change affects KCNJ2 function (PMID: 29874177). 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. - |
Atrial fibrillation, familial, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Andersen Tawil syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Short QT syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2023 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at