Variant: NM_000162.5(GCK):c.46-2A>G

CA367403894

447400 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: c6f3c62e-abc5-43bc-86fb-70c8365c5d8a

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_000162.5:c.46-2A>G
NM_000162.5(GCK):c.46-2A>G
NC_000007.14:g.44153465T>C
CM000669.2:g.44153465T>C
NC_000007.13:g.44193064T>C
CM000669.1:g.44193064T>C
NC_000007.12:g.44159589T>C
NG_008847.1:g.40959A>G
NG_008847.2:g.49706A>G
ENST00000395796.8:c.*44-2A>G
ENST00000616242.5:c.46-2A>G
ENST00000682635.1:n.532-2A>G
ENST00000345378.7:c.49-2A>G
ENST00000403799.8:c.46-2A>G
ENST00000671824.1:c.46-2A>G
ENST00000673284.1:c.46-2A>G
ENST00000345378.6:c.49-2A>G
ENST00000395796.7:c.43-2A>G
ENST00000403799.7:c.46-2A>G
ENST00000437084.1:c.46-2A>G
ENST00000476008.1:n.481-2A>G
ENST00000616242.4:c.43-2A>G
NM_000162.3:c.46-2A>G
NM_033507.1:c.49-2A>G
NM_033508.1:c.43-2A>G
NM_000162.4:c.46-2A>G
NM_001354800.1:c.46-2A>G
NM_033507.2:c.49-2A>G
NM_033508.2:c.43-2A>G
NM_033507.3:c.49-2A>G
NM_033508.3:c.43-2A>G

Pathogenic

• Met criteria codes: PS4 PVS1 PM2_Supporting PP4_Moderate PP1_Strong

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting, PP4_Moderate, PP1_Strong, PS4.

Met criteria codes

• PS4: This variant was identified in 7 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 17573900, 27256595, 30447144; internal lab contributors).
• PVS1: This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting).
• PP4_Moderate: This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595, internal lab contributors).
• PP1_Strong: This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1__Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors).