chr7-44151048-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):āc.391T>Cā(p.Ser131Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,816 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 Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S131S) has been classified as Likely benign.
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.391T>C | p.Ser131Pro | missense_variant | 4/10 | ENST00000403799.8 | |
GCK | NM_033507.3 | c.394T>C | p.Ser132Pro | missense_variant | 4/10 | ||
GCK | NM_033508.3 | c.388T>C | p.Ser130Pro | missense_variant | 5/11 | ||
GCK | NM_001354800.1 | c.391T>C | p.Ser131Pro | missense_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.391T>C | p.Ser131Pro | missense_variant | 4/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727202
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1993 | - - |
Likely pathogenic, criteria provided, single submitter | research | Geisinger Clinic, Geisinger Health System | Aug 02, 2022 | PM2, PP1_Strong, PP4, PP2, PS3_Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 01, 2022 | - - |
Permanent neonatal diabetes mellitus 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 01, 2022 | - - |
Type 2 diabetes mellitus Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 01, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2023 | ClinVar contains an entry for this variant (Variation ID: 16138). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 2555564, 8495817, 36257325; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 131 of the GCK protein (p.Ser131Pro). 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 GCK protein function. 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. Experimental studies have shown that this missense change affects GCK function (PMID: 8325892, 8495817). - |
Hyperinsulinism due to glucokinase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at