PCDH19
protein-codingprotocadherin 19, the group of Non-clustered protocadherins
Gene summary
The protein encoded by this gene is a member of the delta-2 protocadherin subclass of the cadherin superfamily. The encoded protein is thought to be a calcium-dependent cell-adhesion protein that is primarily expressed in the brain. Mutations in this gene on human chromosome X are associated with sporadic infantile epileptic encephalopathy and to a female-restricted form of epilepsy (EFMR; also known as PCDH19RE). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]
- EFMR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~118.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011794
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
The PCDH19 gene has been associated with X-linked epilepsy in the past. Variants in PCDH19 have been reported in humans as early as 2008. Initially, the phenotypic description was that of intellectual disability and seizures with onset in the later part of infancy affecting girls. Subsequently, a broader spectrum of epilepsy phenotypes has emerged, including affected mosaic males. At least 11 variants (missense and de novo) were curated from two publications (19214208, 21480887). While there is no experimental support directly linking the gene to epilepsy, there is reasonable biological plausibility and the mechanism of the unusual sparing of the hemizygous condition has robust experimental support. In summary, there is definitive evidence to support this gene-disease association, replicated over more than a decade at the time of this curation. The Epilepsy Gene Curation Expert Panel has decided to curate this gene for X-linked complex neurodevelopmental disorder (Mondo:0100038) because of the presence of ID/DD and epilepsy. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 9/4/18 (SOP Version 6).
Inheritance Pattern: XL
Disease ID:MONDO:0010246
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010246
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010246
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCDH19 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001184880.2. 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 | 7 | 338 | 2 | 347 | ||
| missense | 44 | 102 | 645 | 54 | 2 | 847 |
| nonsense | 82 | 17 | 3 | 102 | ||
| start loss | 1 | 1 | ||||
| frameshift | 185 | 31 | 6 | 222 | ||
| splice donor/acceptor (+/-2bp) | 10 | 4 | 5 | 19 | ||
| Total | 322 | 154 | 666 | 392 | 4 | 1538 |
Highest pathogenic variant AF is 0.000011848428
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001171809.1 | 6 | MANE Select | |
| Ensembl | ENSP00000362125.4 | 6 | MANE Select | |
| RefSeq | NP_001098713.1 | 5 | Standard | |
| RefSeq | NP_065817.2 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pcdh19 | Danio rerio | Structure: ethmoid cartilage Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cell adhesion
- homophilic cell adhesion via plasma membrane adhesion molecules
- brain development
Molecular Function
- calcium ion binding
Cellular Component
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373034
- Coding exons
- 6
- Length
- 118630
- Individuals with no LoFs
- 124794
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 3
- Defined
- 124798
- p
- 0.0000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.59 | 336 | 499 | 0.673 | 0.0000422 | 7525 |
| Missense (PolyPhen) | 95 | 201.52 | 0.47142 | 2998 | ||
| Synonymous | -0.225 | 222 | 218 | 1.02 | 0.0000195 | 2390 |
| Loss of Function | 4.51 | 0 | 23.7 | 0.00 | 0.00000178 | 381 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000074 | 0.000056 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00023 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Potential calcium-dependent cell-adhesion protein.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 9 (EIEE9) [MIM:300088]: A condition characterized by seizure with onset in infancy or early childhood, cognitive impairment, and delayed development of variable severity in some patients. Additional features include autistic signs and psychosis. The disorder is sex-limited, with the phenotype being restricted to females. {ECO:0000269|PubMed:18469813, ECO:0000269|PubMed:19214208, ECO:0000269|PubMed:19752159, ECO:0000269|PubMed:20713952, ECO:0000269|PubMed:20830798, ECO:0000269|PubMed:21053371, ECO:0000269|PubMed:21480887, ECO:0000269|PubMed:21519002, ECO:0000269|PubMed:22050978, ECO:0000269|PubMed:22267240, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26993267}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.111
Intolerance Scores
- LoFtool
- 0.0992
- RVIS EVS
- -0.89
- RVIS percentile EVS
- 10.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.296
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |