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

CA213745

36192 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
UUID: d79afd5b-fa4f-4521-a81c-e231b58460a6
Approved on: 2023-06-20
Published on: 2023-06-20

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
More

Likely Benign

Met criteria codes 3
BP2 BP4 BP7
Not Met criteria codes 4
BA1 BS1 PS4 PM2

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 1.1.0

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.
Met criteria codes
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.
BP7
No impact on splicing based on SpliceAI, Δ score below 0.2 and phyloP100 way <2.0. (-0.068).
Not Met criteria codes
BA1
gnomAD popmax filtering AF=0.000007310 <0.0001
BS1
gnomAD popmax filtering AF=0.000007310 <0.00004
PS4
No PS4 at any level if not met PM2_Supporting.
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.
Curation History
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