PCDHA12

protein-coding

protocadherin alpha 12, 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_018903.4

Inheritance

—

ClinVar variants

U:167B:20

Top phenotype

PCDHA13-related disorder

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr5:140,875,302-141,012,347

External References & Databases

Ensembl (ENSG00000251664)

Transcript & Mutation Effects

hg38 • Region Span ~137.0 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 PCDHA12 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 559

not providedTotal: 26

PCDHA13-related disorderTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

PCDHA12-related conditionTotal: 1

Hirschsprung disease, susceptibility to, 1Total: 1

PCDHA9-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018903.4. 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			167 clinvar	14 clinvar		181
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	167	19	1	187

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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_018903.4	RefSeq	NP_061726.1	4	MANE Select
ENST00000398631.3	Ensembl	ENSP00000381628.2	4	MANE Select
NM_031864.3	RefSeq	NP_114070.1	1	Standard
ENST00000613593.1	Ensembl	ENSP00000481404.1	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: ENST00000398631
Coding exons: 4
Length: 136872
Individuals with no LoFs: 125179
Homozygous LoFs: 5
Heterozygous LoFs: 564
Defined: 125748
p: 0.00227

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.337	608	585	1.04	0.0000414	6056
Missense (PolyPhen)		160	165.07	0.96926		1939
Synonymous	0.992	264	285	0.925	0.0000250	2046
Loss of Function	0.796	22	26.4	0.833	0.00000131	318

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00072	0.00071	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00044	0.00042	rare
South Asian	0.014	0.014	notable
Other	0.0011	0.00098	notable

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: 0.859
RVIS EVS: 1.23
RVIS percentile EVS: 93.28

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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