7-44146531-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP5

The NM_000162.5(GCK):c.951C>G(p.His317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,610,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: -0.348

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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

PP5

Variant 7-44146531-G-C is Pathogenic according to our data. Variant chr7-44146531-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447426.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5 link	c.951C>G	p.His317Gln	missense_variant	Exon 8 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.951C>G	p.His317Gln	missense_variant	Exon 8 of 10	1	NM_000162.5	ENSP00000384247.3		P35557-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458248

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725700

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the GCK protein (p.His317Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant maturity onset diabetes of the young (PMID: 31063852, 36257325; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447426). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Dec 14, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 36257325, 31063852) -

Maturity-onset diabetes of the young type 2

Pathogenic:1

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP3, PP1_Moderate, PS4_Strong, PM5_Supporting, PP4, PP2 -

not specified

Uncertain:1

Feb 21, 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.951C>G (p.His317Gln) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.951C>G has been reported in the literature in individuals suspected of Monogenic Diabetes (examples: Sanyoura_2019 and Mirshahi_2022). At-least one of these reports classified the variant as VUS (Sanyoura_2019). These reports do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36257325, 31063852). ClinVar contains an entry for this variant (Variation ID: 447426). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1

Uncertain:1

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.37

.;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.70

T;T;.;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

-1.3

.;N;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

0.54

.;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.25

.;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T

Polyphen

0.010

B;B;B;B;.

Vest4

0.15

MutPred

0.41

.;Gain of disorder (P = 0.1464);.;.;.;

MVP

0.75

MPC

1.1

ClinPred

0.15

GERP RS

2.9

Varity_R

0.22

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: -1

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