rs201264306
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000525.4(KCNJ11):c.526C>T(p.Arg176Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,088 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000525.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.526C>T | p.Arg176Cys | missense_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.265C>T | p.Arg89Cys | missense_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.265C>T | p.Arg89Cys | missense_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.265C>T | p.Arg89Cys | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.526C>T | p.Arg176Cys | missense_variant | 1/1 | NM_000525.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248678Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134600
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1460914Hom.: 0 Cov.: 63 AF XY: 0.0000330 AC XY: 24AN XY: 726764
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74344
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
KCNJ11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 13, 2023 | The KCNJ11 c.526C>T variant is predicted to result in the amino acid substitution p.Arg176Cys. This variant has been reported in individuals with diabetes but did not segregate with disease within the family (Edghill EL et al 2004. PubMed ID: 15504982; Flechtner et al 2006. PubMed ID: 17296510). Functional studies using artificial mutation showed that this variant may affect KCNJ11 function (John SA et al 2001. PubMed ID: 11585851). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17409113-G-A). This variant is classified as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/211223/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 176 of the KCNJ11 protein (p.Arg176Cys). This variant is present in population databases (rs201264306, gnomAD 0.009%). This missense change has been observed in individual(s) with diabetes mellitus (PMID: 15504982). ClinVar contains an entry for this variant (Variation ID: 211223). 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 KCNJ11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 11585851). 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. - |
Maturity-onset diabetes of the young type 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 04, 2022 | _x000D_ Criteria applied: PM5_STR, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at