rs556436603

Positions:

chr7-44147690-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePP2PP3PP1PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The c.823C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 275 (p.(Arg275Cys)) of NM_000162.5. This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID:24001579, internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 3 informative meioses in 1 family (PP1; PMID:24001579). 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While a study exploring the effect of this variant on protein function has been performed and suggests a possible impact on stability and dimerization, the study does not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID:24001579). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation, 1 copy in the African/African American subpopulation, and 1 copy in the South Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, 823C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239519/MONDO:0015967/086

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 5.35

Variant links:

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 links:

LOC105375258 (HGNC:):

LOC105375258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS4

PM2

PP1

PP2

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.823C>T	p.Arg275Cys	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3 linkuse as main transcript	n.40G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.823C>T	p.Arg275Cys	missense_variant	7/10	1	NM_000162.5	P1	P35557-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250398

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459898

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726062

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

National Newborn Screening Laboratory, Hospital Nacional de Niños

This is a missense variant located within exon 7 and generates a change from the aminoacid Arginine acid to Cysteine in position 275. It is located in a mutational hot spot (PM1). It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2). It is a missense change at an amino acid residue where a different missense change determined to bepathogenic (c.824G>T) (PM5). Multiple lines of computational evidence support a deleterious effect on the gene (PP3). Missense variant in a gene that has a low rate of benign missense variation for which missense variants are a common mechanism of a disease (PP2). This variant has been reported in the literature associated with individuals with MODY2 (PMID: 19790256, 28371533) but also there is one in vitro functional study supportive of the damaging effect of this variant on the gene (PMID: 24001579) (PS3). -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Sep 20, 2023

The c.823C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 275 (p.(Arg275Cys)) of NM_000162.5. This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 24001579, internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 3 informative meioses in 1 family (PP1; PMID: 24001579). 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While a study exploring the effect of this variant on protein function has been performed and suggests a possible impact on stability and dimerization, the study does not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 24001579). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation, 1 copy in the African/African American subpopulation, and 1 copy in the South Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, 823C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1, PP2, PP3, PM2_Supporting. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;.;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

.;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

1.0

D;D;D;B;.

Vest4

0.93

MutPred

0.82

.;Gain of catalytic residue at L276 (P = 0.0186);.;.;.;

MVP

0.96

MPC

2.5

ClinPred

0.91

GERP RS

5.5

Varity_R

0.79

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over