Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_033508.3:c.676+3A>T

CA2529312623

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: fd93be23-8465-44a6-8548-1808e7aa4fc1

HGVS expressions

NM_033508.3:c.676+3A>T
NC_000007.14:g.44149757T>A
CM000669.2:g.44149757T>A
NC_000007.13:g.44189356T>A
CM000669.1:g.44189356T>A
NC_000007.12:g.44155881T>A
NG_008847.1:g.44667A>T
NG_008847.2:g.53414A>T
ENST00000395796.8:c.*677+3A>T
ENST00000616242.5:c.679+3A>T
ENST00000682635.1:n.1168A>T
ENST00000345378.7:c.682+3A>T
ENST00000403799.8:c.679+3A>T
ENST00000671824.1:c.679+3A>T
ENST00000673284.1:c.679+3A>T
ENST00000345378.6:c.682+3A>T
ENST00000395796.7:c.676+3A>T
ENST00000403799.7:c.679+3A>T
ENST00000437084.1:c.628+3A>T
ENST00000616242.4:c.676+3A>T
NM_000162.3:c.679+3A>T
NM_033507.1:c.682+3A>T
NM_033508.1:c.676+3A>T
NM_000162.4:c.679+3A>T
NM_001354800.1:c.679+3A>T
NM_033507.2:c.682+3A>T
NM_033508.2:c.676+3A>T
NM_000162.5:c.679+3A>T
NM_033507.3:c.682+3A>T

Uncertain Significance

Met criteria codes 2
PP3 PM2_Supporting
Not Met criteria codes 2
PP4 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.679+3A>T variant in the glucokinase gene, GCK, is a noncanonical splice donor site variant in intron 6 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3). This variant was identified in an individual with diabetes; however, the fasting blood glucose was below the threshold (5.5 mmol/L) for PP4 (internal lab contributors). In summary, c.679+3A>T meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PM2_Supporting.
Met criteria codes
PP3
The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
Not Met criteria codes
PP4
This variant was identified in an individual with diabetes; however, the fasting blood glucose was below the threshold (5.5 mmol/L) for PP4 (internal lab contributors).
PS4
This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor).
Approved on: 2024-02-02
Published on: 2024-02-02
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