7-44149763-C-G

Variant names:

• chr7-44149763-C-G
• NM_000162.5:c.676G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_Supporting PP2 PM1 PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367401125/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 7.91

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.676G>C	p.Val226Leu	missense_variant	Exon 6 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.676G>C	p.Val226Leu	missense_variant	Exon 6 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Feb 02, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	.;L;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	.;N;N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.051	.;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		1.0	D;D;D;B;.
Vest4		0.96
MutPred		0.68		.;Loss of catalytic residue at V226 (P = 0.1351);.;.;.;
MVP		0.98
MPC		2.0
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.82
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44189362;