NM_000162.5:c.683C>T

Variant names:

• chr7-44147830-G-A
• rs80356655
• NM_000162.5:c.683C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3_Supporting PM1 PP2 PP3 PM2_Supporting PP4_Moderate PS4 PS2 PM3_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.683C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 228 (p.(Thr228Met)) 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 resides in an amino acid that directly binds glucose and ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In an assay in which the ATPkm was above the MDEP threshold for evaluation of relative activity index (RAI), the Kcat/S0.5 ratio of the Thr228Met variant was 0.0001, which is less than 0.5 of wild type (PS3_Supporting; PMID:11372010). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 26 unrelated individuals with hyperglycemia (PS4; PMIDs: 21720051, 2721189, 36836406, 36723869, 32741144, 34756319, 11372010, 1502186, 31639168, 24323243, internal lab contributors). At least 2 of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID:36723869). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; PMID:24323243). This variant has been detected in one individual with neonatal diabetes who was found to be homozygous for the c.683C>T variant (PM3_Supporting; PMID:11372010). In summary, c.683C>T 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, approved 8/11/2023): PS4, PS2, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA260620/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 9.94
• Publications: 25 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 21 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.683C>T	p.Thr228Met	missense	Exon 7 of 10	NP_000153.1
	GCK	NM_033507.3		c.686C>T	p.Thr229Met	missense	Exon 7 of 10	NP_277042.1
	GCK	NM_033508.3		c.680C>T	p.Thr227Met	missense	Exon 8 of 11	NP_277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.683C>T	p.Thr228Met	missense	Exon 7 of 10	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*681C>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000379142.4
	GCK	ENST00000395796.8	TSL:1	n.*681C>T		3_prime_UTR	Exon 8 of 11	ENSP00000379142.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250034 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726816

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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: 52564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000573 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Maturity-onset diabetes of the young type 2 (4)
2	-	-	Maturity onset diabetes mellitus in young (2)
2	-	-	Permanent neonatal diabetes mellitus 1 (2)
1	-	-	GCK-related disorder (1)
1	-	-	Hyperinsulinism due to glucokinase deficiency (1)
1	-	-	Monogenic diabetes (1)
1	-	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Gain of catalytic residue at M224 (P = 0.0301)
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80356655; hg19: chr7-44187429;