rs199473381
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000891.3(KCNJ2):c.566G>A(p.Arg189Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.566G>A | p.Arg189Lys | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.566G>A | p.Arg189Lys | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.566G>A | p.Arg189Lys | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2022 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 189 of the KCNJ2 protein (p.Arg189Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Anderson-Tawil sydnrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 190812). 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 expected to disrupt KCNJ2 protein function. This variant disrupts the p.Arg189 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 12796536, 27145478), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2013 | p.Arg189Lys (AGA>AAA): c.566 G>A in exon 2 of the KCNJ2 gene (NM_000891.2). The Arg189Lys variant in the KCNJ2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg189Lys results in a conservative amino acid substitution of one positively charged amino acid with another, it occurs at a position that is conserved across species. In silico analysis predicts Arg189Lys is probably damaging to the protein structure/function. Mutations at this codon (Arg189Ile) and in nearby residues (Pro186Leu, Thr192Ala, Thr192Ile) have been reported in association with ATS, further supporting the functional importance of this codon and this region of the protein. Furthermore, the Arg189Lys variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Arg189Lys is a good candidate for a disease-causing mutation, with the information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at