rs193922340
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.952G>T(p.Gly318Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,150 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G318G) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.952G>T | p.Gly318Trp | missense_variant | 8/10 | ENST00000403799.8 | NP_000153.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.952G>T | p.Gly318Trp | missense_variant | 8/10 | 1 | NM_000162.5 | ENSP00000384247 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247698Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134562
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458150Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725650
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2016 | The p.G318W variant (also known as c.952G>T), located in coding exon 8 of the GCK gene, results from a G to T substitution at nucleotide position 952. The glycine at codon 318 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant results in perturbation of the structure as much as known pathogenic variants (Zhang, R., Zhou, M., Peterson, S., Anderson, W., Joachimiak, A. The crystal structure of the adenylosuccinate synthetase from Yersinia pestis CO92. PDB ID: 3HID. http://www.rcsb.org/pdb/explore/explore.do?structureId=3HID). This variant was previously reported in the SNPDatabase as rs193922340. Based on data from the NHLBI Exome Sequencing Project (ESP), no alterations were observed among 13006 alleles tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 06, 2023 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of MODY. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at