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NM_000162.5(GCK):c.45G>A (p.Lys15=) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 26, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003234596.1

Allele description [Variation Report for NM_000162.5(GCK):c.45G>A (p.Lys15=)]

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

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.45G>A (p.Lys15=)
Other names:
NM_000162.5(GCK):c.45G>A; p.Lys15=
HGVS:
  • NC_000007.14:g.44188909C>T
  • NG_008847.2:g.14262G>A
  • NM_000162.3:c.45G>A
  • NM_000162.5:c.45G>AMANE SELECT
  • NM_001354800.1:c.45G>A
  • NP_000153.1:p.Lys15=
  • NP_001341729.1:p.Lys15=
  • LRG_1074t1:c.45G>A
  • LRG_1074:g.14262G>A
  • LRG_1074p1:p.Lys15=
  • NC_000007.13:g.44228508C>T
Molecular consequence:
  • NM_000162.5:c.45G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001354800.1:c.45G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003932642ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.1.0)		Uncertain significance
(May 26, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV003932642.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024