rs370375148
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePP2PP3PM2_SupportingPM5_Supporting
This summary comes from the ClinGen Evidence Repository: The c.749G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 250 (p.(Arg250His)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (pediatric patient with incidental diagnosis with FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persistently and negative antibodies (PP4_Moderate; PMID:28170077, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). Another missense variant, c.748C>T p.Arg250Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg250His (PM5_Supporting). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated, and neither PS3 nor BS3 could be applied (PMID:30592380). In summary, c.749G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239531/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 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 |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.749G>A | p.Arg250His | missense_variant | 7/10 | ENST00000403799.8 | |
LOC105375258 | XR_927223.3 | n.98+16C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.749G>A | p.Arg250His | missense_variant | 7/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251152Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461282Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726972
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Oct 25, 2023 | The c.749G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 250 (p.(Arg250His)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (pediatric patient with incidental diagnosis with FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persistently and negative antibodies (PP4_Moderate; PMID: 28170077, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). Another missense variant, c.748C>T p.Arg250Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg250His (PM5_Supporting). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated, and neither PS3 nor BS3 could be applied (PMID: 30592380). In summary, c.749G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 30, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at