Variant: NM_000162.5(GCK):c.45G>A (p.Lys15=)

CA454592033

2136533 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 0decb226-7ac1-41be-8714-6577d5ba9a38

Approved on: 2023-05-26

Published on: 2023-05-26

HGVS expressions

NM_000162.5:c.45G>A
NM_000162.5(GCK):c.45G>A (p.Lys15=)
NC_000007.14:g.44188909C>T
CM000669.2:g.44188909C>T
NC_000007.13:g.44228508C>T
CM000669.1:g.44228508C>T
NC_000007.12:g.44195033C>T
NG_008847.1:g.5515G>A
NG_008847.2:g.14262G>A
ENST00000616242.5:c.45G>A
ENST00000682635.1:n.531G>A
ENST00000403799.8:c.45G>A
ENST00000671824.1:c.45G>A
ENST00000673284.1:c.45G>A
ENST00000403799.7:c.45G>A
ENST00000437084.1:c.45G>A
ENST00000476008.1:n.480+8782G>A
NM_000162.3:c.45G>A
NM_000162.4:c.45G>A
NM_001354800.1:c.45G>A

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2_Supporting PP3

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 1.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.45G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 15 (p.(Lys15=)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.51 for donor gain and 0.34 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3). This variant was identified in two unrelated individuals with mildly elevated HbA1c that did not require treatment, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19564454, 18248649, internal contributor). One of these individuals has stable impaired fasting glucose, which meets MDEP criteria for PP4, and had negative diabetes autoantibodies (PP4_Moderate; internal contributor) In summary, c.45G>A meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 3/23/23): PM2_Supporting, PP3, PP4_Moderate.

Met criteria codes

• PP4_Moderate: One of these individuals has stable impaired fasting glucose, which meets MDEP criteria for PP4, and had negative diabetes autoantibodies
• PM2_Supporting: This variant is absent from gnomAD v2.1.1
• PP3: It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.51 for donor gain and 0.34 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3).