rs1437510576
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000525.4(KCNJ11):c.794G>T(p.Ser265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S265S) has been classified as Likely benign.
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.794G>T | p.Ser265Ile | missense_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.533G>T | p.Ser178Ile | missense_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.533G>T | p.Ser178Ile | missense_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.533G>T | p.Ser178Ile | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.794G>T | p.Ser265Ile | missense_variant | 1/1 | NM_000525.4 | P1 | ||
KCNJ11 | ENST00000528731.1 | c.533G>T | p.Ser178Ile | missense_variant | 2/2 | 1 | |||
KCNJ11 | ENST00000682350.1 | c.533G>T | p.Ser178Ile | missense_variant | 2/2 | ||||
KCNJ11 | ENST00000682764.1 | c.533G>T | p.Ser178Ile | missense_variant | 2/3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251374Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 67 AF XY: 0.00000413 AC XY: 3AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hyperinsulinemia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Pathogenic variants in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. They are also associated with Neonatal diabetes. However, the significance of S265I (rs1437510576) remains uncertain. - |
KCNJ11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2022 | The KCNJ11 c.794G>T variant is predicted to result in the amino acid substitution p.Ser265Ile. This variant was reported as a variant of uncertain significance in a patient with hyperinsulinism. It was reported to have been inherited from the patient's unaffected father (De Franco et al. 2020. PubMed ID: 32027066). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17408845-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Nov 18, 2016 | ACMG Criteria:PP3, PM2 (NOTE:one European non-Finish in Gnomad) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at