NM_000162.5:c.1120G>C

Variant names:

• chr7-44145630-C-G
• rs1415041911
• NM_000162.5:c.1120G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000162.5(GCK):​c.1120G>C​(p.Val374Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,272 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 (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83

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 10 ACMG points.

• PM1: In a helix (size 35) in uniprot entity HXK4_HUMAN there are 17 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, 0.968
• PP5: Variant 7-44145630-C-G is Pathogenic according to our data. Variant chr7-44145630-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338685.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1120G>C	p.Val374Leu	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1120G>C	p.Val374Leu	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 20, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1120G>C, in exon 9 that results in an amino acid change, p.Val374Leu. The p.Val374Leu change affects a highly conserved amino acid residue located in a domain of the GCK protein that is not known to be functional. The p.Val374Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL). This particular amino acid change does not appear to have been described in the literature in other individuals with GCK related disorders. However, different sequence changes affecting the same amino acid residues (p.Val374Glu and p.Val374Met) have been described in multiple families with MODY (PMID: 19790256). This sequence change has not been described in the population databases such as ExAC and gnomAD. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	.;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.014	.;D;D;D;D;D
Sift4G	Uncertain	0.026	D;T;D;D;D;D
Polyphen		0.73	P;.;D;P;P;P
Vest4		0.88
MutPred		0.87		.;.;Loss of MoRF binding (P = 0.1391);.;.;.;
MVP		0.97
MPC		2.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.99

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: rs1415041911; hg19: chr7-44185229;