rs104894014

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000162.5(GCK):​c.1367C>T​(p.Ala456Val) 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. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

GCK
NM_000162.5 missense

Scores

10
8
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a helix (size 12) in uniprot entity HXK4_HUMAN there are 4 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, 0.982
PP5
Variant 7-44145167-G-A is Pathogenic according to our data. Variant chr7-44145167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16143.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
GCKNM_000162.5 linkuse as main transcriptc.1367C>T p.Ala456Val missense_variant 10/10 ENST00000403799.8 NP_000153.1 P35557-1Q53Y25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkuse as main transcriptc.1367C>T p.Ala456Val missense_variant 10/101 NM_000162.5 ENSP00000384247.3 P35557-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2023For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 11916951, 15987895, 17082186, 17353190, 19146401, 21831042, 22194744). 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: 16143). This missense change has been observed in individuals with hyperinsulinemic hypoglycemia (PMID: 11916951, 14687251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 456 of the GCK protein (p.Ala456Val). -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 12, 2017- -
Hyperinsulinism due to glucokinase deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 2002- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
.;D;D;.;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;.;D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.6
.;.;M;.;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.4
.;D;D;D;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
.;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;T;D;D;D;D
Polyphen
1.0
D;.;P;D;P;P
Vest4
0.85
MutPred
0.92
.;.;Loss of ubiquitination at K459 (P = 0.0573);.;.;.;
MVP
0.98
MPC
1.4
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.93
gMVP
0.98

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.

Other links and lift over

dbSNP: rs104894014; hg19: chr7-44184766; API