PCDH15

protocadherin related 15, the group of Cadherin related|MicroRNA protein coding host genes

Basic information

Region (hg38): 10:53802770-55627942

Previous symbols: [ "USH1F", "DFNB23" ]

Links

ENSG00000150275 ∙ NCBI:65217 ∙ OMIM:605514 ∙ HGNC:14674 ∙ Uniprot:Q96QU1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Usher syndrome type 1F (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 23 (Limited), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 23 (Definitive), mode of inheritance: AR
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• Usher syndrome type 1 (Supportive), mode of inheritance: AR
• Usher syndrome type 1F (Definitive), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 23 (Strong), mode of inheritance: AR
• Usher syndrome type 1F (Strong), mode of inheritance: AR
• Usher syndrome type 1 (Definitive), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 23; Usher syndrome, type 1F; Usher syndrome, type 1D/F, digenic	AR/Digenic	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Ophthalmologic	11398101; 14570705; 15537665; 17653769; 18719945; 19107147
Inheritance can be digenic, involving CDH23

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCDH15 gene.

• not provided (2505 variants)
• Usher syndrome type 1F (677 variants)
• not specified (282 variants)
• Autosomal recessive nonsyndromic hearing loss 23 (156 variants)
• Usher syndrome type 1 (152 variants)
• Inborn genetic diseases (91 variants)
• Usher syndrome type 1D (60 variants)
• Usher syndrome type 1D;Usher syndrome type 1F;Autosomal recessive nonsyndromic hearing loss 23 (31 variants)
• Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1D;Usher syndrome type 1F (25 variants)
• Rare genetic deafness (10 variants)
• PCDH15-related condition (10 variants)
• Retinitis pigmentosa-deafness syndrome (8 variants)
• Usher syndrome (8 variants)
• Nonsyndromic Hearing Loss, Recessive (8 variants)
• Retinal dystrophy (6 variants)
• Usher syndrome type 1D;Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1F (5 variants)
• Hearing impairment (4 variants)
• Usher syndrome type 1F;Usher syndrome type 1D;Autosomal recessive nonsyndromic hearing loss 23 (3 variants)
• Usher syndrome type 1G (2 variants)
• USHER SYNDROME, TYPE ID/F, DIGENIC (2 variants)
• Retinitis pigmentosa (1 variants)
• PCDH15-Related Disorders (1 variants)
• Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1F;Usher syndrome type 1D (1 variants)
• See cases (1 variants)
• Childhood onset hearing loss (1 variants)
• Ear malformation (1 variants)
• Non-Syndromic Hereditary Hearing Impairment (1 variants)
• Nonsyndromic Deafness (1 variants)
• Meniere disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCDH15 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			8	746	7	761
missense		8	787	32	16	843
nonsense	41	47	22	14		124
start loss			1			1
frameshift	80	106	73	47		306
inframe indel			69	24	2	95
splice donor/acceptor (+/-2bp)	4	82	6	1		93
splice region		1	24	109	8	142
non coding		1	32	254	156	443
Total	125	244	998	1118	181

Highest pathogenic variant AF is 0.000118

Variants in PCDH15

This is a list of pathogenic ClinVar variants found in the PCDH15 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-53806431-G-GTCTC			Benign (Dec 18, 2018)
10-53806563-T-G			Likely benign (Oct 26, 2018)
10-53806565-T-C		not specified	Uncertain significance (Aug 05, 2015)
10-53806587-T-A		Usher syndrome type 1F • Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1D;Usher syndrome type 1F	Uncertain significance (Dec 03, 2021)
10-53806633-TTCA-T		Usher syndrome type 1F	Uncertain significance (Apr 02, 2018)
10-53806646-T-G		not specified • Usher syndrome type 1F • Autosomal recessive nonsyndromic hearing loss 23	Benign (Sep 05, 2021)
10-53806678-C-T		not specified	Benign (Nov 02, 2023)
10-53806690-A-ACTGT		Usher syndrome type 1F	Uncertain significance (May 08, 2018)
10-53806692-T-TGTCA		Usher syndrome type 1F	Uncertain significance (Apr 09, 2018)
10-53806693-G-GTCAA		not specified • Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1D;Usher syndrome type 1F	Uncertain significance (Oct 01, 2021)
10-53806710-G-A		Usher syndrome type 1F	Uncertain significance (Aug 17, 2017)
10-53806712-TCAACTGTG-T		Usher syndrome type 1F	Uncertain significance (Nov 08, 2017)
10-53806716-CTG-C		Usher syndrome type 1F	Uncertain significance (Jan 11, 2017)
10-53806748-A-G		Usher syndrome type 1F	Uncertain significance (Jan 24, 2023)
10-53806750-C-T		PCDH15-related disorder	Likely benign (Jan 24, 2024)
10-53806757-T-C		Usher syndrome type 1D	Uncertain significance (Jan 01, 2016)
10-53806756-A-ATTG		Usher syndrome type 1F	Uncertain significance (Oct 13, 2017)
10-53806780-G-A			Uncertain significance (Oct 12, 2016)
10-53806785-A-T		Inborn genetic diseases	Uncertain significance (Aug 10, 2021)
10-53806810-C-CATTT		Usher syndrome type 1F	Uncertain significance (Sep 13, 2017)
10-53806811-A-AT		Usher syndrome type 1F • Autosomal recessive nonsyndromic hearing loss 23	Conflicting classifications of pathogenicity (Jan 24, 2023)
10-53806823-G-GA		Autosomal recessive nonsyndromic hearing loss 23;Usher syndrome type 1D;Usher syndrome type 1F	Uncertain significance (Mar 18, 2022)
10-53806842-A-ATGTGT			Uncertain significance (Jun 26, 2019)
10-53806887-CT-C		Usher syndrome type 1F	Uncertain significance (Apr 11, 2017)
10-53806911-G-A		not specified • PCDH15-related disorder	Conflicting classifications of pathogenicity (Nov 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCDH15	protein_coding	protein_coding	ENST00000361849	33	1825172

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.03e-25	0.994	125198	1	549	125748	0.00219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.68	1196	1.04e+3	1.15	0.0000543	12747
Missense in Polyphen		433	379.09	1.1422		4666
Synonymous	-1.87	422	376	1.12	0.0000206	3970
Loss of Function	3.11	52	82.5	0.630	0.00000468	1011

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0137	0.0138
Ashkenazi Jewish	0.00437	0.00437
East Asian	0.00261	0.00256
Finnish	0.000416	0.000416
European (Non-Finnish)	0.00130	0.00129
Middle Eastern	0.00261	0.00256
South Asian	0.00131	0.00131
Other	0.00163	0.00163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calcium-dependent cell-adhesion protein. Essential for maintenance of normal retinal and cochlear function.
• Disease: DISEASE: Usher syndrome 1F (USH1F) [MIM:602083]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. {ECO:0000269|PubMed:15660226, ECO:0000269|PubMed:22815625}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Usher syndrome 1D/F (USH1DF) [MIM:601067]: USH1DF patients are heterozygous for mutations in CDH23 and PCDH15, indicating a digenic inheritance pattern. {ECO:0000269|PubMed:15537665, ECO:0000269|PubMed:18719945}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 23 (DFNB23) [MIM:609533]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:14570705, ECO:0000269|PubMed:18719945, ECO:0000269|PubMed:28281779}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.178

Intolerance Scores

• loftool: 0.995
• rvis_EVS: 0.74
• rvis_percentile_EVS: 86.35

Haploinsufficiency Scores

• pHI: 0.252
• hipred: Y
• hipred_score: 0.543
• ghis: 0.494

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0375

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Pcdh15
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal phenotype; hearing/vestibular/ear 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); growth/size/body region phenotype; muscle phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: pcdh15a
• Affected structure: neuromast hair cell
• Phenotype tag: abnormal
• Phenotype quality: decreased functionality

Gene ontology

• Biological process: cell adhesion;homophilic cell adhesion via plasma membrane adhesion molecules;sensory perception of sound;photoreceptor cell maintenance;inner ear development;sensory perception of light stimulus;equilibrioception
• Cellular component: photoreceptor outer segment;extracellular region;integral component of plasma membrane;stereocilium;synapse
• Molecular function: calcium ion binding