PCDHA2

protein-coding

protocadherin alpha 2, 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_018905.3

Inheritance

—

ClinVar variants

U:135B:20

Top phenotype

PCDHA9-related disorder

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr5:140,794,852-141,012,347

External References & Databases

Ensembl (ENSG00000204969)

Transcript & Mutation Effects

hg38 • Region Span ~217.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDHA2 variants in ClinVar

12 Conditions Cataloged

not specifiedTotal: 2053

not providedTotal: 92

PCDHA9-related disorderTotal: 35

PCDHA3-related disorderTotal: 15

EBV-positive nodal T- and NK-cell lymphomaTotal: 3

PCDHA13-related disorderTotal: 2

PCDHA2-related disorderTotal: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018905.3. 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				5 clinvar	1 clinvar	6
missense			133 clinvar	14 clinvar		147
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	135	19	1	155

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018905.3	RefSeq	NP_061728.1	4	MANE Select
ENST00000526136.2	Ensembl	ENSP00000431748.1	4	MANE Select
NM_031495.2	RefSeq	NP_113683.1	1	Standard
NM_031496.2	RefSeq	NP_113684.1	2	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
nervous system development

Molecular Function

calcium ion binding

Cellular Component

nucleus
endoplasmic reticulum
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000526136
Coding exons: 4
Length: 217486
Individuals with no LoFs: 125196
Homozygous LoFs: 5
Heterozygous LoFs: 547
Defined: 125748
p: 0.00220

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.742	630	580	1.09	0.0000422	6043
Missense (PolyPhen)		141	146.89	0.95991		1684
Synonymous	-1.56	311	278	1.12	0.0000246	2080
Loss of Function	-0.639	33	29.3	1.13	0.00000150	353

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0022	notable
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00075	0.00071	rare
South Asian	0.013	0.013	notable
Other	0.00098	0.00098	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.;

Recessive Scores

pRec: 0.0947

Intolerance Scores

LoFtool: 0.874
RVIS EVS: 0.01
RVIS percentile EVS: 54.18

Essentials

Essential (CRISPR): N
Indispensability pred.: N
Indispensability score: 0.109

Gene Damage Prediction

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