7-44145602-G-T

Variant names:

• chr7-44145602-G-T
• rs777870079
• NM_000162.5:c.1148C>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000162.5(GCK):​c.1148C>A​(p.Ser383*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,900 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCK NM_000162.5 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 2.43

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44145602-G-T is Pathogenic according to our data. Variant chr7-44145602-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3383914.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1148C>A	p.Ser383*	stop_gained	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.1148C>A	p.Ser383*	stop_gained	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000427 AC: 1 AN: 234324 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128172

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454900 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723714

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Dec 02, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1148C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 383 (p.(Ser383Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 12955723). This variant was identified in another individual with a phenotype suggestive of GCK-hyperglycemia; however, the clinical parameters were not met for PP4 according to ClinGen MDEP VCEP (PhD dissertation by Ovsyannikova [https://iimed.ru/userfiles/models/passages-files/Ovsyannikova_AK_dissertacia.pdf], variant also cited in PMID: 33477506). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 12955723, 33477506, PhD dissertation by Ovsyannikova). In summary, c.1148C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.93
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777870079; hg19: chr7-44185201;