chr7-44145637-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000162.5(GCK):c.1113C>A(p.Cys371Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
GCK
NM_000162.5 stop_gained
NM_000162.5 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.0240
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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 166 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-44145637-G-T is Pathogenic according to our data. Variant chr7-44145637-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 617645.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1113C>A | p.Cys371Ter | stop_gained | 9/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1113C>A | p.Cys371Ter | stop_gained | 9/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 11, 2020 | This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2023 | This sequence change creates a premature translational stop signal (p.Cys371*) 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: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with maturity onset diabetes of the young (PMID: 25555642, 31063852). ClinVar contains an entry for this variant (Variation ID: 617645). For these reasons, this variant has been classified as Pathogenic. - |
Maturity-onset diabetes of the young type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Translational Genomics Laboratory, University of Maryland School of Medicine | Apr 25, 2017 | The c.1113C>A variant in codon 371 (exon 9) of the glucokinase gene, GCK, results in the generation of a stop codon. The c.1113C>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, loss of function nonsense mutations in the GCK gene, including ones in exon 9, have been reported previously in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2) (19790256). Additionally, multiple lines of computational evidence (MutationTaster, LRT, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PVS1, PM2, PP3 - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 09, 2023 | The c.1113C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 371 (p.(Cys371Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9/10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4_Moderate. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at