rs193922289

Positions:

• chr7-44152420-C-G
• chr7-44152420-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):​c.214G>C​(p.Gly72Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_000162.5 (GCK) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 20) in uniprot entity HXK4_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 7-44152420-C-G is Pathogenic according to our data. Variant chr7-44152420-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 976334.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	c.214G>C	p.Gly72Arg	missense_variant	3/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.217G>C	p.Gly73Arg	missense_variant	3/10		NP_277042.1
GCK	NM_033508.3	c.211G>C	p.Gly71Arg	missense_variant	4/11		NP_277043.1
GCK	NM_001354800.1	c.214G>C	p.Gly72Arg	missense_variant	3/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.214G>C	p.Gly72Arg	missense_variant	3/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 04, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 72 of the GCK protein (p.Gly72Arg). 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: 10447526, 12442280, 30259503, 30447144, 30663027, 31216263; Invitae). ClinVar contains an entry for this variant (Variation ID: 976334). 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 expected to disrupt GCK protein function with a positive predictive value of 80%. Studies have shown that this missense change alters GCK gene expression (PMID: 16731834, 17389332). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	.;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.99		.;Loss of sheet (P = 0.1398);.;.;Loss of sheet (P = 0.1398);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		1.0

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

Other links and lift over

dbSNP: rs193922289; hg19: chr7-44192019;