PROK2
protein-codingprokineticin 2, the group of Receptor ligands
Gene summary
This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018800
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018555
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012528
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012528
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012528
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0012528
Submitter: ClinGen
PROK2 was first reported in relation to autosomal dominant Hypogonadotropic hypogonadism 4 with or without anosmia in 2006 (Dodé et al., PMID: 17054399). Hypogonadotropic hypogonadism is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. This can be caused by an isolated defect in gonadotropin-releasing hormone release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, diabetes, sleep disorder, and sensorineural hearing loss, occur with variable frequency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanisms, inheritance patterns, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, hypogonadotropic hypogonadism 4 with or without anosmia (OMIM:610628), Kallman syndrome (KS), and normosic congenital (idiopathic) hypogonadotropic hypogonadism (nIHH) in a semidominant inheritance pattern. Eighteen variants (missense, nonsense, frameshift, duplication, and insertion) that have been reported in 23 probands in 14 publications (PMIDs: 17054399, 17959774, 18559922, 18682503, 18985070, 23082007, 23596439, 24002956, 24031091, 25077900, 26141714, 30098700, 32870266, 33140874) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (animal models, expression studies, biochemical function, and protein interaction) (PMIDs: 12427552, 12604792, 15976302, 17093083, 17959774, 19784373, 24633064). One mouse model phenocopies hypogonadotropic hypogonadism and the expression study demonstrates PROK2 involvement in olfactory bulb neurogenesis. Another mouse model demonstrates that LOF in PROK2 can cause attenuated estrous cycles along with other circadian rhythms including sleep cycles and blood glucose regulation. PROK2 is expressed in the olfactory bulb and testis, proposed to modulate GnRH release as an SCN output molecule regulating circadian rhythms, and interacts with PROKR2 which is definitively associated with hypogonadotropic hypogonadism. In summary, PROK2 is definitively associated with semidominant Hypogonadotropic hypogonadism 4 with or without anosmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This has been approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 03/22/2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0012528
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PROK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001126128.2. 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 | 1 | 15 | 16 | |||
| missense | 1 | 4 | 51 | 2 | 1 | 59 |
| nonsense | 2 | 2 | ||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 2 | 3 | 1 | 6 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 3 | 10 | 57 | 17 | 1 | 88 |
Highest pathogenic variant AF is 0.00023731981
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001119600.1 | 4 | MANE Select | |
| Ensembl | ENSP00000295619.3 | 4 | MANE Select | |
| RefSeq | NP_068754.1 | 3 | Standard | |
| Ensembl | ENSP00000295618.3 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| prok2 | Danio rerio | Structure: sleep Quality: occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling by GPCR
- Signal Transduction
- Peptide ligand-binding receptors
- Class A/1 (Rhodopsin-like receptors)
- GPCR ligand binding
Biological Process
- activation of MAPK activity
- angiogenesis
- chemotaxis
- inflammatory response
- G protein-coupled receptor signaling pathway
Molecular Function
- G protein-coupled receptor binding
Cellular Component
- extracellular region
- cell
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000295619
- Coding exons
- 4
- Length
- 13551
- Individuals with no LoFs
- 125682
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125747
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.261 | 64 | 58.4 | 1.10 | 0.00000308 | 829 |
| Missense (PolyPhen) | 27 | 27.938 | 0.96641 | 380 | ||
| Synonymous | 1.05 | 13 | 18.8 | 0.692 | 8.32e-7 | 255 |
| Loss of Function | 0.592 | 3 | 4.33 | 0.693 | 1.81e-7 | 68 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00042 | 0.00042 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm. May also function locally within the SCN to synchronize output. Potently contracts gastrointestinal (GI) smooth muscle.;
- Disease
- DISEASE: Hypogonadotropic hypogonadism 4 with or without anosmia (HH4) [MIM:610628]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:17054399, ECO:0000269|PubMed:18559922, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in PROK2 as well as in other HH- associated genes including PROKR2 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;
Recessive Scores
- pRec
- 0.122
Intolerance Scores
- LoFtool
- 0.500
- RVIS EVS
- 0.15
- RVIS percentile EVS
- 64.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0192
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |