rs193929376

Variant names:

• chr7-44146461-A-C
• rs193929376
• NM_000162.5:c.1019+2T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM3 PM2_Supporting PVS1 PP1_Strong

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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1019+2T>G		splice_donor_variant, intron_variant	Intron 8 of 9	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1019+2T>G		splice_donor_variant, intron_variant	Intron 8 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.000550 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Oct 08, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Pathogenic:1

Feb 23, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jul 05, 2011

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

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
PhyloP100		8.8
GERP RS		4.4
PromoterAI		0.058	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193929376; hg19: chr7-44186060;