WDPCP

protein-coding

WD repeat containing planar cell polarity effector, the group of Ciliogenesis and planar polarity effector complex subunits

Gene summary

This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Previous symbols:

C2orf86

MANE transcript

NM_015910.7

Inheritance

ClinVar variants

P:62U:395B:199

Top phenotype

Congenital heart defects, hamartomas of tongue, and polysyndactyly; Bardet-Biedl syndrome 15

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr2:63,119,559-63,827,843

External References & Databases

Ensembl (ENSG00000143951)

Transcript & Mutation Effects

hg38 • Region Span ~708.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bardet-Biedl syndrome 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014443

Submitter: G2P

heart defect - tongue hamartoma - polysyndactyly syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009008

Submitter: Ambry Genetics

heart defect - tongue hamartoma - polysyndactyly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009008

Submitter: PanelApp Australia

Bardet-Biedl syndrome 15LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014443

Submitter: Ambry Genetics

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*WDPCP* was first reported in relation to autosomal recessive Bardet-Biedl Syndrome (BBS) in 2010 (Kim et al., PMID: 20671153). Biallelic variants in *WDPCP* were also reported in patients diagnosed with oral-facial-digital syndrome (OFD, PMID: 27158779) and congenital heart defects, hamartomas of tongue, and polysyndactyly (CHDTHP, PMID: 25427950). The WDPCP protein localizes to the base of cilia and the actin cytoskeleton and is required for ciliogenesis (PMID: 24302887). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between the diverse groups off cases. In fact, BBS, OFD, and CHDTHP are all considered part of the larger family of ciliopathies. Therefore, these disease entities have been lumped into one curation under the term WDPCP-related ciliopathy. This curation includes seven variants (one missense, one nonsense, two frameshift, and three splice disruptions) that have been reported in four probands in four publications. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by animal models and cellular studies indicating that loss-of-function in the WDPCP results in ocular and ciliary defects (PMIDs: 24302887, 27158779). In summary, *WDPCP* is definitively associated with autosomal recessive WDPCP-related ciliopathy. This 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 Retina Gene Curation Expert Panel on March 7th, 2024 (SOP Version 10).

Bardet-Biedl syndrome 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014443

Submitter: Labcorp Genetics (formerly Invitae)

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Bardet-Biedl syndrome 15LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014443

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Congenital heart defects, hamartomas of tongue, and polysyndactyly; Bardet-Biedl syndrome 15AR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Endocrine

Rationale: Congenital heart defects, hamartomas of tongue, and polysyndactyly can include congenital cardiac anomalies, and awareness may allow early identification and management; In Bardet-Biedl syndrome, medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Comments: Variants may modify severity of BBS and related disorders due to variants in other BBS-associated genes

Refs: 20671153; 25427950; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDPCP variants in ClinVar

16 Conditions Cataloged

Bardet-Biedl syndromeTotal: 540

WDPCP-related disorderTotal: 366

Bardet-Biedl syndrome 15Total: 203

Heart defect - tongue hamartoma - polysyndactyly syndromeTotal: 172

Inborn genetic diseasesTotal: 97

not specifiedTotal: 87

not providedTotal: 72

Optic atrophyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015910.7. 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			6 clinvar	165 clinvar		171
missense		1 clinvar	378 clinvar	34 clinvar		413
nonsense	2 clinvar	11 clinvar	2 clinvar			15
start loss		1 clinvar	1 clinvar			2
frameshift	11 clinvar	14 clinvar	2 clinvar			27
splice donor/acceptor (+/-2bp)	3 clinvar	19 clinvar	6 clinvar			28
Total	16	46	395	199	0	656

Highest pathogenic variant AF is 0.00023374772

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015910.7	RefSeq	NP_056994.3	18	MANE Select
ENST00000272321.12	Ensembl	ENSP00000272321.7	18	MANE Select
NM_001042692.3	RefSeq	NP_001036157.1	12	Standard
NM_001354044.2	RefSeq	NP_001340973.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wdpcp	Danio rerio	Structure: pigment cell Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

wdpcp

Danio rerio

Structure: pigment cell

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

kidney development
auditory receptor cell morphogenesis
smoothened signaling pathway
regulation of fibroblast migration
regulation of embryonic cell shape

Cellular Component

plasma membrane
axoneme
cell cortex
apical plasma membrane
axonemal basal plate

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000272321
Coding exons: 18
Length: 706460
Individuals with no LoFs: 124667
Homozygous LoFs: 1
Heterozygous LoFs: 123
Defined: 124791
p: 0.000497

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.898	345	395	0.873	0.0000197	4892
Missense (PolyPhen)		110	144.97	0.7588		1928
Synonymous	-0.489	151	144	1.05	0.00000713	1414
Loss of Function	2.68	23	41.6	0.552	0.00000210	493

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00033	0.00032	rare
Latino/Admixed American	0.0016	0.0015	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000094	0.000093	rare
European (Non-Finnish)	0.00037	0.00037	rare
South Asian	0.00049	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable effector of the planar cell polarity signaling pathway which regulates the septin cytoskeleton in both ciliogenesis and collective cell movements. Together with FUZ and WDPCP proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (By similarity). {ECO:0000250|UniProtKB:Q32NR9, ECO:0000250|UniProtKB:Q8C456}.;
Disease: DISEASE: Bardet-Biedl syndrome 15 (BBS15) [MIM:615992]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:20671153}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital heart defects, hamartomas of tongue, and polysyndactyly (CHDTHP) [MIM:217085]: A disease characterized by a constellation of anomalies including tongue hamartomas, polysyndactyly, and congenital heart defects such as atrioventricular canal and coarctation of the aorta. {ECO:0000269|PubMed:25427950, ECO:0000269|PubMed:27158779}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Mutations in WDPCP may act as modifiers of the phenotypic expression of Bardet-Biedl syndrome and Meckel syndrome by interacting in trans with primary BBS and MKS loci. {ECO:0000269|PubMed:20671153}.;

Intolerance Scores

RVIS EVS: 0.47
RVIS percentile EVS: 78.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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