GeneBe

PROKR2

protein-coding

prokineticin receptor 2, the group of Prokineticin receptors

Gene summary

Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins. [provided by RefSeq, Jul 2008]

Previous symbols:
  • GPR73L1
  • KAL3

MANE transcript

NM_144773.4

Inheritance

AD, AR

ClinVar variants

P:22U:147B:66

Top phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr20:5,299,218-5,316,954

External References & Databases

Ensembl (ENSG00000101292)NCBI Gene (128674)OMIM (607123)HGNC:15836GenCCUniProt (Q8NFJ6)AlphaFoldClinVar (PROKR2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~17.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 3 with or without anosmiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009482

Submitter: Ambry Genetics

hypogonadotropic hypogonadism 3 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009482

Submitter: PanelApp Australia

hypogonadotropic hypogonadism 3 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009482

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet

septooptic dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: Orphanet

hypogonadotropic hypogonadism 3 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009482

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

hypogonadotropic hypogonadism 3 with or without anosmiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009482

Submitter: ClinGen

*PROKR2* was first reported in relation to syndromic hypogonadotropic hypogonadism with/without anosmia in 2006 (Dode et al., PMID 17054399). At least 11 missense variants and one frameshift/truncating variant have been reported in humans. Evidence supporting this gene-disease relationship include case level data and experimental data. Excluding variants found as homozygotes in gnomAD and cases with possible digenic inheritance, variants in this gene have been reported in at least 15 probands in 2 publications (PMIDs: 17054399, 18559922) with all cases demonstrating some combination of anosmia and hypogonadotropic hypogonadism. Although the prevalence is not yet clear, patients with *PROKR2* variants who have been subject to neuroimaging demonstrate aplasia of the olfactory apparatus in several instances (PMID: 18559922). Imaging based ascertainment strategies (PMID: 23386640) have also identified *PROKR2* variants in patients with clinical and/or imaging findings in the spectrum of septooptic dysplasia (septal deficiency, pituitary hypoplasia, optic nerve hypoplasia, schizencephaly, callosal agenesis). *PROKR2* related hypogonadotropic hypogonadism is hypothesized to result from interaction with other gene products as overexpression of variant alleles does not squelch function of co-expressed wild type protein (PMID: 18826963). Experimental data for the disease-gene relationship include animal models, in vitro studies of biochemical function, and cell culture assays using non-patient derived cells. More experimental evidence is available in the literature but not cited here. In summary, *PROKR2* is definitively associated with autosomal dominant hypogonadotropic hypogonadism with or without anosmia though prevalence of congenital structural abnormalities of the brain and interaction with other gene variants is not yet fully understood. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 4/26/2022 (SOP Version 8).

hypogonadotropic hypogonadism 3 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009482

Submitter: PanelApp Australia

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 3 with or without anosmiaAD/AR

Manifestation: Craniofacial; Endocrine; Neurologic

Intervention: Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required

Comments: Digenic inheritance (with KAL1) has been reported

Refs: 17054399; 20301509Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PROKR2 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 138
Hypogonadotropic hypogonadism 3 with or without anosmiaTotal: 119
not specifiedTotal: 50
Inborn genetic diseasesTotal: 40
PROKR2-related disorderTotal: 20
AmenorrheaTotal: 3
Male infertility with azoospermia or oligozoospermia due to single gene mutationTotal: 2
Hypogonadotropic hypogonadismTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144773.4. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
48
clinvar
3
clinvar
 53
missense
1
clinvar
13
clinvar
143
clinvar
15
clinvar
 172
nonsense
2
clinvar
1
clinvar
 3
start loss
0
frameshift
2
clinvar
3
clinvar
1
clinvar
 6
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total418147633235

Highest pathogenic variant AF is 0.0011517754

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_144773.4RefSeqNP_658986.12MANE Select
ENST00000678254.1EnsemblENSP00000504128.12MANE Select
ENST00000217270.4EnsemblENSP00000217270.32Standard
ENST00000217270.5EnsemblENSP00000217270.32Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • GPCRs, Other
  • Signaling by GPCR
  • Signal Transduction
  • Peptide ligand-binding receptors
  • Class A/1 (Rhodopsin-like receptors)

Biological Process

  • G protein-coupled receptor signaling pathway
  • neuropeptide signaling pathway
  • circadian rhythm

Molecular Function

  • G protein-coupled receptor activity
  • neuropeptide Y receptor activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000546004
Coding exons
2
Length
15062
Individuals with no LoFs
125705
Homozygous LoFs
0
Heterozygous LoFs
43
Defined
125748
p
0.000171
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1192382331.020.00001582543
Missense (PolyPhen)6172.4960.84142766
Synonymous-0.90910694.71.120.00000681774
Loss of Function0.25099.850.9144.33e-7120

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000320.00032rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.000220.00022rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor for prokineticin 2. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase.;

Recessive Scores

pRec
0.134

Intolerance Scores

LoFtool
0.504
RVIS EVS
-0.22
RVIS percentile EVS
37.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.156

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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