7-44147689-C-T

Position:

chr7-44147689-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPS4_ModeratePM5_SupportingPP2

This summary comes from the ClinGen Evidence Repository: The c.824G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 275 (p.(Arg275His)) of NM_000162.5. This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002940 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). 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 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID:30592380). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID:30592380, internal lab contributors). Another missense variant, c.823C>T p.Arg275His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275His (PM5_Supporting). In summary, c.824G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239518/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 4.02

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

PP2

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 linkuse as main transcript	c.824G>A	p.Arg275His	missense_variant	7/10	ENST00000403799.8	NP_000153.1	P35557-1Q53Y25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.824G>A	p.Arg275His	missense_variant	7/10	1	NM_000162.5	ENSP00000384247.3		P35557-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250116

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135328

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459568

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725914

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 07, 2023

Variant summary: GCK c.824G>A (p.Arg275His) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.824G>A has been reported in the literature in at-least one Asian individual with Gestational Diabetes (example, Wang__2018 cited in Wang_2019 and Zhou_2020). These report(s) do not provide unequivocal conclusions about association of the variant with GCK associated-Monogenic Diabetes. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 70% of normal catalytic activity and no difference in thermal stability relative to wild-type in vitro (Wang_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28371533, 30592380, 32375122). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Monogenic diabetes

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Nov 23, 2023

The c.824G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 275 (p.(Arg275His)) of NM_000162.5. This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002940 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). 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 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30592380). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 30592380, internal lab contributors). Another missense variant, c.823C>T p.Arg275His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275His (PM5_Supporting). In summary, c.824G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PM2_Supporting, PM5_Supporting. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2017

The R275H variant in the GCK gene has been reported previously in a female with gestational diabetes (Wang et al., 2017). The R275H variant is observed in 1/65,196 (0.0015%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). The R275H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant at the same residue has been reported in individuals with MODY (Negahdar et al., 2014; Haliloglu et al., 2016) and missense variants in nearby residues (D274H, D274G, D274V, D274E, L276P, D278E, E279Q, E279G, and S280N) have also been reported in the Human Gene Mutation Database in association with MODY and gestational diabetes (Stenson et al., 2014), supporting the functional importance of this residue. We interpret R275H as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

.;D;.;.;.

Eigen

Benign

0.071

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

D;D;.;D;T

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.53

D;D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.5

.;L;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.3

.;N;N;N;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.022

.;D;D;D;D

Sift4G

Uncertain

0.040

D;D;D;D;D

Polyphen

0.085

B;B;B;B;.

Vest4

0.41

MutPred

0.56

.;Loss of stability (P = 0.0457);.;.;.;

MVP

0.96

MPC

1.3

ClinPred

0.90

GERP RS

5.5

Varity_R

0.66

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