chr7-44145173-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.1361C>T(p.Ala454Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,766 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
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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000417 AC: 1AN: 239696Hom.: 0 AF XY: 0.00000764 AC XY: 1AN XY: 130906
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457766Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725134
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
The c.1361C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 454 (p.(Ala454Val)) of NM_000162.5. 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.916, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other 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). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; PMIDs: 34746319, 36257325). Another missense variant, c.1361C>A p.Ala454Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1361C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at