7-44147678-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BA1

This summary comes from the ClinGen Evidence Repository: The c.835G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 279 (p.(Glu279Gln)) 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 Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000112, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). This variant was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 8446612, PMID 24097065, PMID 30245511, internal lab contributor). This variant has a REVEL score of 0.698, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. While functional studies exploring the effect of this mutation on the gene have been assessed, these studies do not meet the criteria set forth by the MDEP for application of PS3 or BS3 (PMID:8446612). In summary, c.835G>C meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): BA1, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA208420/MONDO:0015967/086

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:4

Conservation

PhyloP100: 4.98

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 Benign. Variant got -7 ACMG points.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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 link	c.835G>C	p.Glu279Gln	missense_variant	Exon 7 of 10	ENST00000403799.8	NP_000153.1	P35557-1Q53Y25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 link	c.835G>C	p.Glu279Gln	missense_variant	Exon 7 of 10	1	NM_000162.5	ENSP00000384247.3		P35557-1

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000112

AC:

AN:

249438

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134942

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1458306

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725032

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.0000448

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.000492

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.000327

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

Alfa

AF:

0.0000364

Hom.:

Bravo

AF:

0.000567

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:2

Nov 04, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK c.835G>C (p.Glu279Gln) results in a conservative amino acid change located in the Hexokinase, C-terminal (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 249438 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GCK causing Maturity-Onset Diabetes Of The Young Type 2 phenotype (2.5e-05). c.835G>C has been reported in the literature in individuals in the context of Monogenic Diabetes (Gidh-Jain_1993, Flannick_2013, Elashi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity-Onset Diabetes Of The Young Type 2. At least one publication reports experimental evidence evaluating an impact on protein function (Gidh-Jain_1993, Veiga-da-Cunha_1996), however the impact of these studies is unclear at this time. The following publications have been ascertained in the context of this evaluation (PMID: 14517946, 9078243, 36613572, 24097065, 8446612, 9049484, 8897004). ClinVar contains an entry for this variant (Variation ID: 211076). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Nov 11, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu278Gln (also known as p.Glu279Gln) variant in GCK is classified as likely benign because it has been identified in 0.16% (39/24916) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. ACMG/AMP Criteria applied: BS1. -

Jun 12, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity-onset diabetes of the young type 2

Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency

Uncertain:1

Jan 11, 2023

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes

Benign:1

Jun 21, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.835G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 279 (p.(Glu279Gln)) 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 Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000112, which is greater than the MDEP threshold for BA1 (>=0.0001) (BA1). This variant was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 8446612, PMID 24097065, PMID 30245511, internal lab contributor). This variant has a REVEL score of 0.698, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. While functional studies exploring the effect of this mutation on the gene have been assessed, these studies do not meet the criteria set forth by the MDEP for application of PS3 or BS3 (PMID: 8446612). In summary, c.835G>C meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): BA1, PP2. -

not provided

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;T;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.36

T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.8

.;L;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.56

.;N;N;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.23

.;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.93

P;P;P;B;.

Vest4

0.85

MVP

0.94

MPC

2.0

ClinPred

0.075

GERP RS

5.5

Varity_R

0.63

gMVP

0.97

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

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