rs193929376

Positions:

• chr7-44146461-A-C
• chr7-44146461-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2_Supporting PP1_Strong PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The c.1019+2T>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363). This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4. This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3). In summary, the evidence supports the classification of c.1019+2T>G as a pathogenic variant for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PVS1, PM3, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA341584/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 8.77

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]

GCK (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1019+2T>G		splice_donor_variant, intron_variant		ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1019+2T>G		splice_donor_variant, intron_variant		1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00211 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	The c.1019+2 T>G splice site variant in the GCK gene has been previously reported to segregate with disease in two related families with MODY and permanent neonatal diabetes (Njølstad et al., 2003; Shehadeh et al., 2005). This variant destroys the canonical splice donor site in intron 8, and is expected to cause abnormal gene splicing. The variant is not observed in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2020	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Feb 23, 2024

The c.1019+2T>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363). This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4. This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3). In summary, the evidence supports the classification of c.1019+2T>G as a pathogenic variant for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PVS1, PM3, PP1_Strong. -

Permanent neonatal diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Jul 05, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 0
DS_DL_spliceai		0.96		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193929376; hg19: chr7-44186060;