rs193922340

Variant summary

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

The NM_000162.5(GCK):​c.952G>T​(p.Gly318Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,150 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: 0.0000014 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

13
5
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 7-44146530-C-A is Pathogenic according to our data. Variant chr7-44146530-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36268.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.952G>T p.Gly318Trp missense_variant 8/10 ENST00000403799.8 NP_000153.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkuse as main transcriptc.952G>T p.Gly318Trp missense_variant 8/101 NM_000162.5 ENSP00000384247 P1P35557-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000807
AC:
2
AN:
247698
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134562
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:
0.0000327
Gnomad FIN exome
AF:
0.0000529
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458150
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
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:
0.0000116
Gnomad4 FIN exome
AF:
0.0000201
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -
Maturity onset diabetes mellitus in young Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 06, 2016The p.G318W variant (also known as c.952G>T), located in coding exon 8 of the GCK gene, results from a G to T substitution at nucleotide position 952. The glycine at codon 318 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant results in perturbation of the structure as much as known pathogenic variants (Zhang, R., Zhou, M., Peterson, S., Anderson, W., Joachimiak, A. The crystal structure of the adenylosuccinate synthetase from Yersinia pestis CO92. PDB ID: 3HID. http://www.rcsb.org/pdb/explore/explore.do?structureId=3HID). This variant was previously reported in the SNPDatabase as rs193922340. Based on data from the NHLBI Exome Sequencing Project (ESP), no alterations were observed among 13006 alleles tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJul 06, 2023The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of MODY. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
.;D;.;.;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D;D;.;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-7.3
.;D;D;D;D
REVEL
Pathogenic
0.90
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
0.84
MutPred
0.88
.;Loss of disorder (P = 0.0132);.;.;.;
MVP
0.94
MPC
2.3
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.98
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: rs193922340; hg19: chr7-44186129; API