rs193922329
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000162.5(GCK):c.76C>T(p.Gln26Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GCK
NM_000162.5 stop_gained
NM_000162.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.25
Genes affected
GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 612 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-44153433-G-A is Pathogenic according to our data. Variant chr7-44153433-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.76C>T | p.Gln26Ter | stop_gained | 2/10 | ENST00000403799.8 | |
GCK | NM_033507.3 | c.79C>T | p.Gln27Ter | stop_gained | 2/10 | ||
GCK | NM_033508.3 | c.73C>T | p.Gln25Ter | stop_gained | 3/11 | ||
GCK | NM_001354800.1 | c.76C>T | p.Gln26Ter | stop_gained | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.76C>T | p.Gln26Ter | stop_gained | 2/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461734Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727162
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1461734
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34
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AN XY:
727162
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 24735133, 11508276, 24804978, 28726111). ClinVar contains an entry for this variant (Variation ID: 36256). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 24323243). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11508276, 14981344, 25525159, 24735133) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 21, 2020 | - - |
Maturity-onset diabetes of the young type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Geisinger Clinic, Geisinger Health System | Aug 02, 2022 | PVS1, PM2, PP1, PS4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | National Newborn Screening Laboratory, Hospital Nacional de Niños | - | This is a nonsense variant in the GCK gene, where loss of function is a known mechanism of disease (PVS1). This variant results in a truncated protein by creating a premature stop codon. It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2). - |
Maturity onset diabetes mellitus in young Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs193922329 in MODY, yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at