7-44145602-G-C

Variant names:

• chr7-44145602-G-C
• NM_000162.5:c.1148C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PP2 PP3 PM5 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1148C>G variant in the glucokinase gene, GCK, causes an amino acid change of serine to tryptophan at codon 383 (p. (Ser383Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 located in the larger hexokinase domain of the GCK gene (PMID:31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1148C>T (p.Ser383Leu), has been interpreted as pathogenic by the ClinGen MDEP, and p.Ser383Trp has an equal or greater Grantham distance (PM5). This variant was found in one family, and segregated with hyperglycemia, with four informative meioses (PP1_Moderate; PMID:3385223). In summary, c.1148C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PP2, PP1_Moderate, PM5, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398735/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 2.43

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1148C>G	p.Ser383Trp	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1148C>G	p.Ser383Trp	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Feb 28, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1148C>G variant in the glucokinase gene, GCK, causes an amino acid change of serine to tryptophan at codon 383 (p. (Ser383Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1148C>T (p.Ser383Leu), has been interpreted as pathogenic by the ClinGen MDEP, and p.Ser383Trp has an equal or greater Grantham distance (PM5). This variant was found in one family, and segregated with hyperglycemia, with four informative meioses (PP1_Moderate; PMID: 3385223). In summary, c.1148C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PP2, PP1_Moderate, PM5, PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	.;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.77
MutPred		0.83		.;.;Loss of disorder (P = 0.004);.;.;.;
MVP		0.98
MPC		2.5
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr7-44185201;