NM_000162.5:c.1358_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT

Variant names:

• chr7-44145009-GGCCTGGGTCCTGACAAGGCCAGGCCTCCTGCCCCGCCAGGCTGCGAGCACGTGTGGGGAGCACTTCCCCATGGAGCCTGGGTGCTGTGGGGCTGTGGCATCCTCCCTGCGCTTGCGGCCACTGCTCTCACTGGCCCAGCATACAGGCCTTCTTACAGGCCACCGCCG-A
• NM_000162.5:c.1358_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT

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.1358_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT​(p.Ser453fs) variant causes a frameshift, stop lost, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S453S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 frameshift, stop_lost, synonymous
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.862

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: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44145009-GGCCTGGGTCCTGACAAGGCCAGGCCTCCTGCCCCGCCAGGCTGCGAGCACGTGTGGGGAGCACTTCCCCATGGAGCCTGGGTGCTGTGGGGCTGTGGCATCCTCCCTGCGCTTGCGGCCACTGCTCTCACTGGCCCAGCATACAGGCCTTCTTACAGGCCACCGCCG-A is Pathogenic according to our data. Variant chr7-44145009-GGCCTGGGTCCTGACAAGGCCAGGCCTCCTGCCCCGCCAGGCTGCGAGCACGTGTGGGGAGCACTTCCCCATGGAGCCTGGGTGCTGTGGGGCTGTGGCATCCTCCCTGCGCTTGCGGCCACTGCTCTCACTGGCCCAGCATACAGGCCTTCTTACAGGCCACCGCCG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2571664.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.1358_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT	p.Ser453fs	frameshift_variant, stop_lost, synonymous_variant	Exon 10 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_000162.5	c.1356_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT		3_prime_UTR_variant	Exon 10 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1358_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT	p.Ser453fs	frameshift_variant, stop_lost, synonymous_variant	Exon 10 of 10	1	NM_000162.5	ENSP00000384247.3
GCK	ENST00000403799	c.1356_*127delCGGCGGTGGCCTGTAAGAAGGCCTGTATGCTGGGCCAGTGAGAGCAGTGGCCGCAAGCGCAGGGAGGATGCCACAGCCCCACAGCACCCAGGCTCCATGGGGAAGTGCTCCCCACACGTGCTCGCAGCCTGGCGGGGCAGGAGGCCTGGCCTTGTCAGGACCCAGGCCinsT		3_prime_UTR_variant	Exon 10 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Jun 20, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1358_*127del168insT variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 453 (NM_000162.5), adding 25 novel amino acids before encountering a stop codon (p.(S453LfsX25)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 could not be evaluated due to lack of clinical information (internal lab contributor). PS4_Moderate also cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, c.1358_*127del168insT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44184608;