PCDH19

protocadherin 19, the group of Non-clustered protocadherins

Basic information

Region (hg38): X:100291643-100410273

Previous symbols: [ "EFMR" ]

Links

ENSG00000165194 ∙ NCBI:57526 ∙ OMIM:300460 ∙ HGNC:14270 ∙ Uniprot:Q8TAB3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 9 (Definitive), mode of inheritance: XL
• Dravet syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 9 (Supportive), mode of inheritance: Unknown
• developmental and epileptic encephalopathy, 9 (Definitive), mode of inheritance: XL
• developmental and epileptic encephalopathy, 9 (Strong), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epileptic encephalopathy, early infantile, 9	XL	General	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	Neurologic	18469813; 19214208; 19752159; 20830798; 20713952; 21519002; 21777234; 22050978; 22267240; 22633638; 22848613; 22949144
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCDH19 gene.

• Developmental and epileptic encephalopathy, 9 (928 variants)
• not provided (317 variants)
• Inborn genetic diseases (96 variants)
• not specified (95 variants)
• Seizure (4 variants)
• Non-ketotic hyperglycinemia;Developmental and epileptic encephalopathy, 9 (4 variants)
• PCDH19-related condition (3 variants)
• Neurodevelopmental disorder with epilepsy (2 variants)
• Intellectual disability (2 variants)
• History of neurodevelopmental disorder (2 variants)
• sporadic NAFE (2 variants)
• Non-lesional parietal lobe epilepsy (1 variants)
• Abnormal cerebral morphology (1 variants)
• Neurodevelopmental delay (1 variants)
• PCDH19-related epilepsy (1 variants)
• 11 conditions (1 variants)
• Childhood epilepsy with centrotemporal spikes (1 variants)
• developmental delay with seizures (1 variants)
• Complex febrile seizure (1 variants)
• Epileptic encephalopathy (1 variants)
• Familial GGE (1 variants)
• PCDH19-related epilespy (1 variants)
• Focal-onset seizure (1 variants)
• Paroxysmal choreoathetosis;Paroxysmal dyskinesia;Chorea;Sleep abnormality;Choreoathetosis (1 variants)
• Autism spectrum disorder (1 variants)
• Bilateral tonic-clonic seizure (1 variants)
• Developmental and epileptic encephalopathy, 1 (1 variants)
• Developmental and epileptic encephalopathy, 9;Non-ketotic hyperglycinemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCDH19 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			6	228	4	238
missense	31	58	426	19	1	535
nonsense	72	9	1			82
start loss		1				1
frameshift	143	14	8			165
inframe indel	2	3	14		1	20
splice donor/acceptor (+/-2bp)	7	4	1			12
splice region	1		3	5		9
non coding			1	20	7	28
Total	255	89	457	267	13

Highest pathogenic variant AF is 0.0000179

Variants in PCDH19

This is a list of pathogenic ClinVar variants found in the PCDH19 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-100296269-A-G		not specified	Benign (May 22, 2014)
X-100296285-C-G		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jul 12, 2022)
X-100296285-C-T		not specified • Developmental and epileptic encephalopathy, 9 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 22, 2023)
X-100296285-CG-C		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jan 13, 2022)
X-100296287-A-G		Developmental and epileptic encephalopathy, 9 • Inborn genetic diseases	Uncertain significance (Jun 20, 2023)
X-100296286-G-GAT		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jun 16, 2021)
X-100296287-A-ATATCCT		Developmental and epileptic encephalopathy, 9	Uncertain significance (Dec 05, 2022)
X-100296292-C-G			Uncertain significance (Nov 14, 2022)
X-100296293-T-C			Uncertain significance (Jan 21, 2020)
X-100296300-G-A		Developmental and epileptic encephalopathy, 9	Uncertain significance (Dec 24, 2021)
X-100296302-T-C		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jun 13, 2022)
X-100296303-T-C		Developmental and epileptic encephalopathy, 9	Uncertain significance (Mar 16, 2023)
X-100296308-C-T		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jul 18, 2023)
X-100296309-C-T		not specified • Developmental and epileptic encephalopathy, 9 • PCDH19-related disorder	Likely benign (Jan 14, 2023)
X-100296312-G-A		Developmental and epileptic encephalopathy, 9 • not specified • Inborn genetic diseases • PCDH19-related disorder	Benign/Likely benign (Jan 17, 2024)
X-100296318-CTT-C		Developmental and epileptic encephalopathy, 9	Uncertain significance (Oct 04, 2023)
X-100296319-T-C		not specified • Developmental and epileptic encephalopathy, 9	Conflicting classifications of pathogenicity (Nov 10, 2022)
X-100296324-T-G		not specified • Developmental and epileptic encephalopathy, 9 • Inborn genetic diseases	Benign (Jan 26, 2024)
X-100296326-C-T		Developmental and epileptic encephalopathy, 9	Uncertain significance (Nov 08, 2022)
X-100296331-T-C		Developmental and epileptic encephalopathy, 9	Likely benign (Dec 27, 2023)
X-100296340-A-C		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jan 31, 2020)
X-100296345-G-A		Developmental and epileptic encephalopathy, 9	Uncertain significance (Jan 17, 2024)
X-100296354-C-G		Developmental and epileptic encephalopathy, 9	Uncertain significance (Mar 06, 2020)
X-100296357-G-A		not specified	Uncertain significance (Dec 20, 2017)
X-100296360-T-G		Developmental and epileptic encephalopathy, 9	Uncertain significance (Nov 24, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCDH19	protein_coding	protein_coding	ENST00000373034	6	118630

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000250	124794	1	3	124798	0.0000160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.59	336	499	0.673	0.0000422	7525
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000738	0.0000556
Finnish	0.00	0.00
European (Non-Finnish)	0.0000256	0.0000177
Middle Eastern	0.0000738	0.0000556
South Asian	0.00	0.00
Other	0.000225	0.000165

dbNSFP

Source: dbNSFP

• 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

Haploinsufficiency Scores

• pHI: 0.380
• hipred: Y
• hipred_score: 0.809
• ghis: 0.572

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.296

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pcdh19
• Phenotype: cellular 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: pcdh19
• Affected structure: ethmoid cartilage
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: cell adhesion;homophilic cell adhesion via plasma membrane adhesion molecules;brain development
• Cellular component: integral component of plasma membrane
• Molecular function: calcium ion binding