rs149127157
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_004982.4(KCNJ8):c.821G>A(p.Arg274His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274C) has been classified as Uncertain significance.
Frequency
Consequence
NM_004982.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ8 | NM_004982.4 | c.821G>A | p.Arg274His | missense_variant | 3/3 | ENST00000240662.3 | |
LOC105369689 | XR_007063241.1 | n.631+6092C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ8 | ENST00000240662.3 | c.821G>A | p.Arg274His | missense_variant | 3/3 | 1 | NM_004982.4 | P1 | |
ENST00000542489.1 | n.107-179C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251280Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135822
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727216
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74300
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 274 of the KCNJ8 protein (p.Arg274His). This variant is present in population databases (rs149127157, gnomAD 0.01%). This missense change has been observed in individual(s) with KCNJ8-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 216600). 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 KCNJ8 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2021 | The p.R274H variant (also known as c.821G>A), located in coding exon 2 of the KCNJ8 gene, results from a G to A substitution at nucleotide position 821. The arginine at codon 274 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at