PROK2

prokineticin 2, the group of Receptor ligands

Basic information

Region (hg38): 3:71771655-71785206

Links

ENSG00000163421 ∙ NCBI:60675 ∙ OMIM:607002 ∙ HGNC:18455 ∙ Uniprot:Q9HC23 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 4 with or without anosmia (Strong), mode of inheritance: AD
• hypogonadotropic hypogonadism 4 with or without anosmia (Strong), mode of inheritance: AR
• hypogonadotropic hypogonadism 4 with or without anosmia (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 4 with or without anosmia	AD/AR/Digenic	Endocrine	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	Craniofacial; Endocrine; Neurologic	17054399; 17959774; 18285834; 20301509

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PROK2 gene.

• not provided (2 variants)
• PROK2-related disorder (1 variants)
• Hypogonadotropic hypogonadism 4 with or without anosmia (1 variants)
• Male infertility with azoospermia or oligozoospermia due to single gene mutation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PROK2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	3		4
missense		2	17	1	1	21
nonsense			1			1
start loss			1			1
frameshift	2		1			3
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1			2
splice region				1		1
non coding			1	10	8	19
Total	2	3	23	14	9

Highest pathogenic variant AF is 0.000112

Variants in PROK2

This is a list of pathogenic ClinVar variants found in the PROK2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-71772503-A-C			Likely benign (Jan 07, 2019)
3-71772559-TA-T			Benign (Aug 10, 2019)
3-71772559-TAA-T			Likely benign (Aug 13, 2019)
3-71772559-T-TA			Benign (Aug 18, 2019)
3-71772588-A-G			Likely benign (Jun 19, 2018)
3-71772722-G-A		not specified	Benign (Sep 13, 2018)
3-71772733-G-C		PROK2-related disorder	Likely benign (Mar 06, 2023)
3-71772749-C-T		PROK2-related disorder • Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
3-71772750-G-A			Uncertain significance (Sep 05, 2021)
3-71772751-G-T		PROK2-related disorder	Uncertain significance (Apr 03, 2024)
3-71772782-G-T			Benign (Nov 27, 2023)
3-71772801-G-A		Male infertility with spermatogenesis disorder	Likely pathogenic (Sep 01, 2023)
3-71772804-G-A		PROK2-related disorder	Uncertain significance (Aug 30, 2024)
3-71772812-C-T		PROK2-related disorder	Uncertain significance (Feb 08, 2022)
3-71772813-G-A		PROK2-related disorder	Uncertain significance (Dec 09, 2019)
3-71772816-CA-C		Inborn genetic diseases • PROK2-related disorder	Uncertain significance (Oct 19, 2022)
3-71772816-C-CA		not specified • PROK2-related disorder • Hypogonadotropic hypogonadism 4 with or without anosmia	Conflicting classifications of pathogenicity (Jan 24, 2024)
3-71772818-A-G		PROK2-related disorder	Likely benign (Dec 08, 2022)
3-71772833-A-T		PROK2-related disorder	Likely benign (Oct 17, 2023)
3-71773105-G-A			Benign (May 28, 2019)
3-71774207-C-G			Likely benign (Oct 24, 2018)
3-71774431-C-T		not specified	Benign (Jan 29, 2024)
3-71774432-G-A			Likely benign (Aug 30, 2023)
3-71774503-T-C		Inborn genetic diseases	Uncertain significance (May 18, 2023)
3-71774509-T-C		PROK2-related disorder	Uncertain significance (May 06, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PROK2	protein_coding	protein_coding	ENST00000295619	4	13551

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0138	0.689	125682	0	65	125747	0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.261	64	58.4	1.10	0.00000308	829
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000359	0.000358
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000422	0.000422
Middle Eastern	0.00	0.00
South Asian	0.000131	0.000131
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Signaling by GPCR;Signal Transduction;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;G alpha (q) signalling events;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.122

Intolerance Scores

• loftool: 0.500
• rvis_EVS: 0.15
• rvis_percentile_EVS: 64.11

Haploinsufficiency Scores

• pHI: 0.331
• hipred: N
• hipred_score: 0.241
• ghis: 0.492

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0192

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prok2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: prok2
• Affected structure: sleep
• Phenotype tag: abnormal
• Phenotype quality: occurrence

Gene ontology

• Biological process: activation of MAPK activity;angiogenesis;chemotaxis;inflammatory response;G protein-coupled receptor signaling pathway;positive regulation of cytosolic calcium ion concentration;neuropeptide signaling pathway;spermatogenesis;circadian rhythm;cell population proliferation;positive regulation of cell population proliferation;sensory perception of pain;negative regulation of apoptotic process;regulation of angiogenesis;positive regulation of smooth muscle contraction
• Cellular component: extracellular region;cell
• Molecular function: G protein-coupled receptor binding