ENST00000459642.1:n.390C>A

Variant names:

• chr7-44145740-G-T
• rs193922257
• ENST00000459642.1:n.390C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PP4_Moderate PP1_Strong

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 ENST00000459642.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: -0.334
• Publications: 0 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: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000459642.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.1020-10C>A		intron	N/A	NP_000153.1
	GCK	NM_033507.3		c.1023-10C>A		intron	N/A	NP_277042.1
	GCK	NM_033508.3		c.1017-10C>A		intron	N/A	NP_277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000459642.1	TSL:1	n.390C>A		non_coding_transcript_exon	Exon 1 of 2
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.1020-10C>A		intron	N/A	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*1018-10C>A		intron	N/A	ENSP00000379142.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 191258 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 32932

American (AMR) AF: 0.00 AC: 0 AN: 41142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38276

South Asian (SAS) AF: 0.00 AC: 0 AN: 83126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100122

Other (OTH) AF: 0.00 AC: 0 AN: 59376

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

Oct 04, 2016

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 36169). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant is not present in population databases (gnomAD no frequency). 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.

Monogenic diabetes Pathogenic:1

Feb 02, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jan 25, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 23, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		-0.33
PromoterAI		-0.075	Neutral

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

Other links and lift over

dbSNP: rs193922257; hg19: chr7-44185339;