rs193922278

Positions:

• chr7-44145227-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS4_Moderate PP1_Strong PS3_Supporting PM5_Supporting PP4_Moderate PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1307T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 436 (p.(Ile436Asn)) 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 is also predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 17204055, PMID 20337973, PMID 22493702, internal lab contributors). At least 2 of these individuals have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies +/- 2 hour oral glucose tolerance test increment <3 mmol/L) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). Another missense variant, c.1306A>T p.Ile436Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). While the RAI of this variant was 0.975, this variant results in decreased inhibition by GKRP (PS3_Supporting; PMID:22493702). In summary, this evidence supports the classification of c.1307T>A as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213751/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.79

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]

GCK (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.
• 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1307T>A	p.Ile436Asn	missense_variant	10/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1307T>A	p.Ile436Asn	missense_variant	10/10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 27, 2024

The c.1307T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 436 (p.(Ile436Asn)) 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 is also predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 17204055, PMID 20337973, PMID 22493702, internal lab contributors). At least 2 of these individuals have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies +/- 2 hour oral glucose tolerance test increment <3 mmol/L) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). Another missense variant, c.1306A>T p.Ile436Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). While the RAI of this variant was 0.975, this variant results in decreased inhibition by GKRP (PS3_Supporting; PMID: 22493702). In summary, this evidence supports the classification of c.1307T>A as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;D;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.9	.;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.95
MutPred		0.94		.;.;Gain of disorder (P = 0.0117);.;.;.;
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193922278; hg19: chr7-44184826;