GCKR

protein-coding

glucokinase regulator

Gene summary

This gene encodes a protein belonging to the GCKR subfamily of the SIS (Sugar ISomerase) family of proteins. The gene product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells by binding non-covalently to form an inactive complex with the enzyme. This gene is considered a susceptibility gene candidate for a form of maturity-onset diabetes of the young (MODY). [provided by RefSeq, Jul 2008]

MANE transcript

NM_001486.4

Inheritance

—

ClinVar variants

P:1U:182B:50

Top phenotype

FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 5

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr2:27,496,839-27,523,684

External References & Databases

Ensembl (ENSG00000084734)

Transcript & Mutation Effects

hg38 • Region Span ~26.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GCKR variants in ClinVar

5 Conditions Cataloged

not providedTotal: 213

not specifiedTotal: 74

FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 5Total: 11

GCKR-related disorderTotal: 7

HypertriglyceridemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001486.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	30 clinvar	5 clinvar	40
missense		1 clinvar	151 clinvar	11 clinvar	1 clinvar	164
nonsense			8 clinvar	1 clinvar		9
start loss						0
frameshift			8 clinvar	2 clinvar		10
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	1	182	44	6	233

Highest pathogenic variant AF is 0.00002974667

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001486.4	RefSeq	NP_001477.2	19	MANE Select
ENST00000264717.7	Ensembl	ENSP00000264717.2	19	MANE Select
ENST00000411584.1	Ensembl	ENSP00000416917.1	7	Standard
ENST00000453813.1	Ensembl	ENSP00000399463.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gckr	Danio rerio	Structure: pancreatic B cell Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

gckr

Danio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt Signaling Pathway
Metabolism of carbohydrates
Metabolism
Regulation of Glucokinase by Glucokinase Regulatory Protein
Glycolysis

Biological Process

obsolete protein import into nucleus, translocation
carbohydrate metabolic process
regulation of glycolytic process
response to fructose
negative regulation of glucokinase activity

Molecular Function

enzyme inhibitor activity
protein binding
enzyme binding
carbohydrate binding
fructose-6-phosphate binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264717
Coding exons: 19
Length: 26846
Individuals with no LoFs: 125166
Homozygous LoFs: 0
Heterozygous LoFs: 582
Defined: 125748
p: 0.00232

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.14	399	340	1.17	0.0000200	4077
Missense (PolyPhen)		82	82.992	0.98805		1067
Synonymous	-0.980	146	132	1.11	0.00000777	1256
Loss of Function	0.832	31	36.4	0.851	0.00000213	385

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0033	0.0033	notable
Ashkenazi Jewish	0.0087	0.0088	notable
East Asian	0.0018	0.0019	notable
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.0024	0.0023	notable
South Asian	0.0011	0.0011	notable
Other	0.0037	0.0038	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits glucokinase (GCK) by forming an inactive complex with this enzyme. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6- phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity. {ECO:0000269|PubMed:23621087, ECO:0000269|PubMed:23733961}.;

Recessive Scores

pRec: 0.187

Intolerance Scores

LoFtool: 0.325
RVIS EVS: -0.73
RVIS percentile EVS: 14.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.475

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium