7-44146530-C-T

Position:

chr7-44146530-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000162.5(GCK):c.952G>A(p.Gly318Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G318G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.76

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a region_of_interest Hexokinase large subdomain (size 239) in uniprot entity HXK4_HUMAN there are 61 pathogenic changes around while only 2 benign (97%) in NM_000162.5

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-44146530-C-T is Pathogenic according to our data. Variant chr7-44146530-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.952G>A	p.Gly318Arg	missense_variant	8/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.952G>A	p.Gly318Arg	missense_variant	8/10	1	NM_000162.5	ENSP00000384247	P1	P35557-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458148

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725650

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 23, 2021	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced affinity of the enzyme to glucose (PMID: 28842611). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 585929). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 12627330, 22493702, 28663157, 29207974). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21348868, 33852230, 26641800, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 31416898, 30245511, 23433541, 34440516, 34556497, 22332836) -

Monogenic diabetes

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2021	Variant summary: GCK c.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247788 control chromosomes. c.952G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes presenting as MODY2 (Maturity Onset Diabetes of the Young) (example, Thomson_2003, Pruhova_2003, Feigeriova_2006, Dustakova_2012, Valentinova_2012, Gal_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 18, 2021	- -

GCK-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The GCK c.952G>A variant is predicted to result in the amino acid substitution p.Gly318Arg. This variant is predicted to alter splicing by strengthening a cryptic splice site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751; Alamut Visual v1.6.1). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported in individuals with maturity-onset diabetes of the young and noted to segregate with disease in several families (Pruhova et al. 2003. PubMed ID: 12627330; Dusatkova et al. 2012. PubMed ID: 22332836; Wędrychowicz et al. 2017. PubMed ID: 28663157). In addition, it has been reported as a founder variant in individuals of Czech ancestry (Dusatkova et al. 2012. PubMed ID: 22332836). A different missense variant affecting the same amino acid (p.Glu318Ala), has been reported in an individual with maturity-onset diabetes of the young (Gloyn. 2003. PubMed ID: 14517946). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;.;.

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.3

.;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.93

MutPred

0.92

.;Gain of solvent accessibility (P = 0.0078);.;.;.;

MVP

0.94

MPC

2.2

ClinPred

1.0

GERP RS

3.9

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.71

Position offset: -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