7-44153363-G-T

Variant names:

• chr7-44153363-G-T
• rs193922286
• NM_000162.5:c.146C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_Moderate PM2_Supporting PP2 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.146C>A variant in the glucokinase gene, GCK causes an amino acid change of threonine to asparagine at codon 49 (p.(Thr49Asn)) of NM_000162.5. 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 has a REVEL score of 0.691, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on GCK function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, this number does not meet the MDEP cutoff for PS4_Moderate (PMID:30257192, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 7 informative meioses in 2 families (PP1_Strong; PMID:30257192, internal lab contributors). Functional studies demonstrated the p.Thr49Asn protein had a relative activity index (RAI) < 0.5; however, the wild-type kinetic parameters didn’t pass the MDEP quality control, and PS3_Moderate could not be applied (PMID:30257192). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023): PP1_Strong, PP4_Moderate, PM2_Supporting, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213765/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.03

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 8 ACMG points.

• PM2: 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.
• PP4: 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.146C>A	p.Thr49Asn	missense_variant	Exon 2 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.149C>A	p.Thr50Asn	missense_variant	Exon 2 of 10		NP_277042.1
GCK	NM_033508.3	c.143C>A	p.Thr48Asn	missense_variant	Exon 3 of 11		NP_277043.1
GCK	NM_001354800.1	c.146C>A	p.Thr49Asn	missense_variant	Exon 2 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.146C>A	p.Thr49Asn	missense_variant	Exon 2 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Monogenic diabetes Pathogenic:1

Aug 13, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.146C>A variant in the glucokinase gene, GCK causes an amino acid change of threonine to asparagine at codon 49 (p.(Thr49Asn)) of NM_000162.5. 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 has a REVEL score of 0.691, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on GCK function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, this number does not meet the MDEP cutoff for PS4_Moderate (PMID: 30257192, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 7 informative meioses in 2 families (PP1_Strong; PMID: 30257192, internal lab contributors). Functional studies demonstrated the p.Thr49Asn protein had a relative activity index (RAI) < 0.5; however, the wild-type kinetic parameters didn’t pass the MDEP quality control, and PS3_Moderate could not be applied (PMID: 30257192). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023): PP1_Strong, PP4_Moderate, PM2_Supporting, PP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;.;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	.;D;D;D;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.016	.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;D;P;.
Vest4		0.66
MutPred		0.35		.;Loss of phosphorylation at T49 (P = 0.0131);.;.;Loss of phosphorylation at T49 (P = 0.0131);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.73
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs193922286; hg19: chr7-44192962;