PCDHA9

protein-coding

protocadherin alpha 9, the group of Clustered protocadherins

Gene summary

This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_031857.2

Inheritance

ClinVar variants

U:169B:50

Top phenotype

PCDHA9-related disorder

gnomAD constraint

pLI —, LoF o/e 1.2

Max pathogenic AF

—

Genomic locus

chr5:140,847,772-141,012,347

External References & Databases

Ensembl (ENSG00000204961)

Transcript & Mutation Effects

hg38 • Region Span ~164.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0004976

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDHA9 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 1054

not providedTotal: 59

PCDHA9-related disorderTotal: 35

EBV-positive nodal T- and NK-cell lymphomaTotal: 2

PCDHA13-related disorderTotal: 2

Prostate cancerTotal: 1

PCDHA12-related conditionTotal: 1

ThrombocytosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031857.2. 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				28 clinvar	3 clinvar	31
missense			169 clinvar	17 clinvar	1 clinvar	187
nonsense				1 clinvar		1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	169	46	4	219

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031857.2	RefSeq	NP_114063.1	4	MANE Select
ENST00000532602.2	Ensembl	ENSP00000436042.2	4	MANE Select
NM_014005.5	RefSeq	NP_054724.1	1	Standard
ENST00000378122.4	Ensembl	ENSP00000367362.3	1	Standard

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

Molecular Function

calcium ion binding

Cellular Component

integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000532602
Coding exons: 4
Length: 164882
Individuals with no LoFs: 125447
Homozygous LoFs: 26
Heterozygous LoFs: 275
Defined: 125748
p: 0.00120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.55	678	573	1.18	0.0000426	6065
Missense (PolyPhen)		233	209.71	1.111		2467
Synonymous	-1.60	312	278	1.12	0.0000252	2062
Loss of Function	-0.991	33	27.4	1.20	0.00000142	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0.011	0.0096	notable
Latino/Admixed American	0.0021	0.0019	notable
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00049	0.00049	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00038	0.00033	rare
South Asian	0.00099	0.00091	rare
Other	0.00083	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.;

Intolerance Scores

LoFtool: 0.893
RVIS EVS: 1.5
RVIS percentile EVS: 95.39

Essentials

Essential (CRISPR): N
Indispensability pred.: N
Indispensability score: 0.161

Gene Damage Prediction

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