7-44145618-C-T

Position:

• chr7-44145618-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2_Supporting PS4 PP1_Strong PM5_Supporting PP4_Moderate PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1132G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 378 (p.(Ala378Thr) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, it is absent in multiple large population cohorts (UKBiobank, BioMe, Geisinger, internal lab contributors) and therefore the ClinGen MDEP has approved the application of PM2_Supporting for this variant (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1133C>T (p.(Ala378Val)), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala378Thr (PM5_Supporting). Additionally, GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been identified in over 30 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 18248649, PMID 16965331, internal lab contributors). This variant segregates with diabetes in 15 informative meioses in a large extended family with diabetes (PP1_Strong; internal lab contributor). 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 negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1132G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PM5_Supporting, PP2, PS4, PP1_Strong, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA126216/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 3.27

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 14 ACMG points.

• 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.1132G>A	p.Ala378Thr	missense_variant	9/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1132G>A	p.Ala378Thr	missense_variant	9/10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454616 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 07, 2023

The c.1132G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 378 (p.(Ala378Thr) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, it is absent in multiple large population cohorts (UKBiobank, BioMe, Geisinger, internal lab contributors) and therefore the ClinGen MDEP has approved the application of PM2_Supporting for this variant (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1133C>T (p.(Ala378Val)), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala378Thr (PM5_Supporting). Additionally, GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been identified in over 30 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 18248649, PMID 16965331, internal lab contributors). This variant segregates with diabetes in 15 informative meioses in a large extended family with diabetes (PP1_Strong; internal lab contributor). 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 negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1132G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PM5_Supporting, PP2, PS4, PP1_Strong, PP4_moderate. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16145). This missense change has been observed in individual(s) with GCK-related conditions (PMID: 16965331, 18248649). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 378 of the GCK protein (p.Ala378Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;.;H;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.1	.;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;D;D
Vest4		0.93
MutPred		0.98		.;.;Gain of phosphorylation at A378 (P = 0.0884);.;.;.;
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
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: rs104894016; hg19: chr7-44185217;