chr11-17387931-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PM2PM5PP3_StrongBP6
The NM_000525.4(KCNJ11):c.161G>A(p.Arg54His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,246 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54C) has been classified as Pathogenic.
Frequency
Consequence
NM_000525.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.161G>A | p.Arg54His | missense_variant | 1/1 | ENST00000339994.5 | NP_000516.3 | |
KCNJ11 | NM_001166290.2 | c.-16-85G>A | intron_variant | NP_001159762.1 | ||||
KCNJ11 | NM_001377296.1 | c.-16-85G>A | intron_variant | NP_001364225.1 | ||||
KCNJ11 | NM_001377297.1 | c.-16-85G>A | intron_variant | NP_001364226.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251096Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135706
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458246Hom.: 0 Cov.: 63 AF XY: 0.00000276 AC XY: 2AN XY: 724586
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 13 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 15, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 54 of the KCNJ11 protein (p.Arg54His). This variant is present in population databases (rs587783666, gnomAD 0.0009%). This missense change has been observed in individual(s) with congenital hyperinsulinism (PMID: 23345197). ClinVar contains an entry for this variant (Variation ID: 158673). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNJ11 protein function with a positive predictive value of 95%. 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. - |
Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 24, 2014 | - - |
Hyperinsulinemic hypoglycemia Benign:1
Benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which is responsive to oral sulfonylureas. This particular variant rs587783666 is associated with persistent hyperinsulinemic hypoglycemia of infancy. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at