7-44149763-C-T

Variant names:

• chr7-44149763-C-T
• rs148311934
• NM_000162.5:c.676G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PP2 PP3 PS3_Moderate PM2_Supporting PP4_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with 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; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID:10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0​). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213827/MONDO:0015967/086

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.91
• Publications: 22 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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 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.
• PM1: 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.676G>A	p.Val226Met	missense	Exon 6 of 10	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.679G>A	p.Val227Met	missense	Exon 6 of 10	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.673G>A	p.Val225Met	missense	Exon 7 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.676G>A	p.Val226Met	missense	Exon 6 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*674G>A		non_coding_transcript_exon	Exon 7 of 11	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000395796.8	TSL:1	n.*674G>A		3_prime_UTR	Exon 7 of 11	ENSP00000379142.4	A0A8C8KJG0

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251402 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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727140

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

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

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000478 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Maturity-onset diabetes of the young type 2 (4)
3	-	-	Maturity-onset diabetes of the young (3)
3	-	-	not provided (3)
2	-	-	Monogenic diabetes (2)
1	-	-	GCK-related disorder (1)
1	-	-	Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.86		Gain of loop (P = 0.2045)
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.86
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: rs148311934; hg19: chr7-44189362; COSMIC: COSV60787716; COSMIC: COSV60787716;