Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000162.5(GCK):c.1285A>C (p.Arg429=)

CA213745

36192 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d79afd5b-fa4f-4521-a81c-e231b58460a6

HGVS expressions

NM_000162.5:c.1285A>C

NM_000162.5(GCK):c.1285A>C (p.Arg429=)

NC_000007.14:g.44145249T>G

CM000669.2:g.44145249T>G

NC_000007.13:g.44184848T>G

CM000669.1:g.44184848T>G

NC_000007.12:g.44151373T>G

NG_008847.1:g.49175A>C

NG_008847.2:g.57922A>C

ENST00000395796.8:c.*1283A>C

ENST00000616242.5:c.*405A>C

ENST00000683378.1:n.511A>C

ENST00000336642.9:c.319A>C

ENST00000345378.7:c.1288A>C

ENST00000403799.8:c.1285A>C

ENST00000671824.1:c.1348A>C

ENST00000672743.1:n.297A>C

ENST00000673284.1:c.1285A>C

ENST00000336642.8:n.337A>C

ENST00000345378.6:c.1288A>C

ENST00000395796.7:c.1282A>C

ENST00000403799.7:c.1285A>C

ENST00000437084.1:c.1234A>C

ENST00000459642.1:n.665A>C

ENST00000616242.4:n.1282A>C

NM_000162.3:c.1285A>C

NM_033507.1:c.1288A>C

NM_033508.1:c.1282A>C

NM_000162.4:c.1285A>C

NM_001354800.1:c.1285A>C

NM_001354801.1:c.274A>C

NM_001354802.1:c.145A>C

NM_001354803.1:c.319A>C

NM_033507.2:c.1288A>C

NM_033508.2:c.1282A>C

NM_033507.3:c.1288A>C

NM_033508.3:c.1282A>C

NM_001354803.2:c.319A>C

Likely Benign

BP7 BP2 BP4

PM2 BS1 PS4 BA1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1285A>C variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 429 (p.(Arg429=)) of NM_000162.5. The Popmax filtering frequency of the c.1285A>C variant in gnomAD v2.1.1 is 0.000007310, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.068, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has been observed in unknown phase with the variant c.106C>T p.Arg36Trp, which is classified as likely pathogenic by the ClinGen MDEP (BP2). In summary, c.1285A>C meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): BP2, BP4, BP7.

BP7

No impact on splicing based on SpliceAI, Δ score below 0.2 and phyloP100 way <2.0. (-0.068).

BP2

This variant has been observed in unknown phase with the variant c.106C>T p.Arg36Trp, which is classified as likely pathogenic by the ClinGen MDEP (BP2).

BP4

SpliceAI score of 0.1 for Acceptor loss, 0.03 for Acceptor gain, which is below the MDEP cutoff of 0.2.

PM2

The Popmax frequency of the c.1285A>C variant in gnomAD v2.1.1 is 0.000007310, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

BS1

gnomAD popmax filtering AF=0.000007310 <0.00004

PS4

No PS4 at any level if not met PM2_Supporting.

BA1

gnomAD popmax filtering AF=0.000007310 <0.0001

Approved on: 2023-06-20

Published on: 2023-06-20

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