chr7-44153465-T-C

Position:

• chr7-44153465-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM2_Supporting PS4 PP1_Strong PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID:19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID:27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as 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, PP4_Moderate, PP1_Strong, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367403894/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.89

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 19 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.46-2A>G		splice_acceptor_variant, intron_variant		ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.49-2A>G		splice_acceptor_variant, intron_variant			NP_277042.1
GCK	NM_033508.3	c.43-2A>G		splice_acceptor_variant, intron_variant			NP_277043.1
GCK	NM_001354800.1	c.46-2A>G		splice_acceptor_variant, intron_variant			NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.46-2A>G		splice_acceptor_variant, intron_variant		1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 03, 2025

The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as 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, PP4_Moderate, PP1_Strong, PS4. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554335966 in MODY, yet. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: -11
DS_AL_spliceai		0.99		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: rs1554335966; hg19: chr7-44193064;