rs587780345

Variant names:

• chr7-44150004-C-T
• rs587780345
• NM_000162.5:c.544G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2 PP3 PP1 PM2_Supporting PS3_Moderate PP4_Moderate PS4

This summary comes from the ClinGen Evidence Repository: The c.544G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 182 (p.(Val182Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting).This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional assays were performed where the MDEP wild type quality control measures were met, and showed that the relative activity Index (RAI) of this variant was 0.02, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID:10525657). Furthermore, this variant was identified in at least 12 unrelated individuals with hyperglycemia (PS4; PMID:8433729, 10754480, 14517956, 25306193, 29510678, 31968686, 34496959, 35737141). At least one 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 macrosomia in normoglycemic offspring) (PP4_Moderate; PMID:34406393). Additionally, this variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; PMIDs: 25494859, 29510678). In summary, c.544G>A 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 08/11/2023): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS3_Moderate, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152954/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.91
• Publications: 19 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

Specifications for GCK are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: 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.
• PP2: 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: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.544G>A	p.Val182Met	missense	Exon 5 of 10	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.547G>A	p.Val183Met	missense	Exon 5 of 10	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.541G>A	p.Val181Met	missense	Exon 6 of 11	NP_277043.1	P35557-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.544G>A	p.Val182Met	missense	Exon 5 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*542G>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000395796.8	TSL:1	n.*542G>A		3_prime_UTR	Exon 6 of 11	ENSP00000379142.4	A0A8C8KJG0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461660 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000460 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
2	-	-	Maturity-onset diabetes of the young (2)
2	-	-	Maturity-onset diabetes of the young type 2 (2)
1	-	-	Gestational diabetes (1)
1	-	-	Monogenic diabetes (1)
1	-	-	Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1833104:Permanent neonatal diabetes mellitus;C1865290:Hyperinsulinism due to glucokinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587780345; hg19: chr7-44189603;