PCDHAC1

protein-coding

protocadherin alpha subfamily C, 1, 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_018898.5

Inheritance

—

ClinVar variants

U:127B:14

Top phenotype

PCDHA13-related disorder

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr5:140,926,299-141,012,347

External References & Databases

Ensembl (ENSG00000248383)

Transcript & Mutation Effects

hg38 • Region Span ~86.0 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 PCDHAC1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 232

not providedTotal: 14

PCDHA13-related disorderTotal: 2

Hirschsprung disease, susceptibility to, 1Total: 1

PCDHA9-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018898.5. 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				4 clinvar	1 clinvar	5
missense			127 clinvar	9 clinvar		136
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	127	13	1	141

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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_018898.5	RefSeq	NP_061721.2	4	MANE Select
ENST00000253807.3	Ensembl	ENSP00000253807.2	4	MANE Select
NM_031882.4	RefSeq	NP_114088.2	1	Standard
ENST00000409700.4	Ensembl	ENSP00000386356.3	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
nervous system development

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: ENST00000253807
Coding exons: 4
Length: 85628
Individuals with no LoFs: 125449
Homozygous LoFs: 0
Heterozygous LoFs: 299
Defined: 125748
p: 0.00119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.00543	552	552	1.00	0.0000296	6227
Missense (PolyPhen)		162	151.4	1.07		1856
Synonymous	1.40	205	232	0.883	0.0000131	2079
Loss of Function	1.47	20	28.5	0.702	0.00000164	321

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0030	0.0029	notable
Latino/Admixed American	0.0021	0.0021	notable
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00038	0.00038	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.00049	0.00049	rare
Other	0.0012	0.0011	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.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.976
RVIS EVS: 1.23
RVIS percentile EVS: 93.27

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.259

Gene Damage Prediction

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