chr7-44145740-G-T

Position:

• chr7-44145740-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP1_Strong PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1020-10C>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.95 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 8 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, three-generation, dominant family history of diabetes or hyperglycemia, and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1020-10C>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): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213703/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_000162.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: -0.334

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1020-10C>A		splice_polypyrimidine_tract_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.1020-10C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1423470 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 706772

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	The GCK c.1020-10C>A variant (rs193922257), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 36169). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is variant in the splice acceptor region of intron 8, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Different variants affecting this splice region have been identified in MODY patients (Garin 2018). However, given the lack of clinical and functional data, the significance of the c.1020-10C>A variant is uncertain at this time. References: Garin I et al. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf). 2008 Jun;68(6):873-8. PMID: 18248649. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	This sequence change falls in intron 8 of the GCK gene. It does not directly change the encoded amino acid sequence of the GCK protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of GCK-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 36169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 04, 2016	- -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Feb 02, 2024

The c.1020-10C>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.95 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 8 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, three-generation, dominant family history of diabetes or hyperglycemia, and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1020-10C>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): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2019

Variant summary: GCK c.1020-10C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing (ACMG PP3): Two predict the variant abolishes the canonical 3' acceptor site. Three predict the variant weakens the canonical 3' acceptor site. Five predict the variant creates a novel 3' acceptor site in intron 8. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 187084 control chromosomes (gnomAD, ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1020-10C>A in individuals affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Maturity-onset diabetes of the young type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 1.00). The variant has been reported to be associated with GCK related disorder (ClinVar ID: VCV000036169). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2
DS_AL_spliceai		0.95		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922257; hg19: chr7-44185339;