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

Likely Benign

• Met criteria codes: BP7 BP2 BP4

• Not Met criteria codes: PS4 BA1 PM2 BS1

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.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

• 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.

Not Met criteria codes

• PS4: No PS4 at any level if not met PM2_Supporting.
• BA1: gnomAD popmax filtering AF=0.000007310 <0.0001
• 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