PCDHGA12

protein-coding

protocadherin gamma subfamily A, 12, the group of Clustered protocadherins

Gene summary

This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

Previous symbols:

CDH21

MANE transcript

NM_003735.3

Inheritance

—

ClinVar variants

U:135B:14

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr5:141,430,507-141,512,975

External References & Databases

Ensembl (ENSG00000253159)

Transcript & Mutation Effects

hg38 • Region Span ~82.5 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 PCDHGA12 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 351

Inborn genetic diseasesTotal: 104

not providedTotal: 30

Neurodevelopmental disorder with poor growth and skeletal anomaliesTotal: 11

PCDHGC4-related disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003735.3. 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				7 clinvar	2 clinvar	9
missense			134 clinvar	5 clinvar		139
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	135	12	2	149

Highest pathogenic variant AF is 0.0000043382875

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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_003735.3	RefSeq	NP_003726.1	4	MANE Select
ENST00000252085.4	Ensembl	ENSP00000252085.3	4	MANE Select
NM_032094.2	RefSeq	NP_115265.1	1	Standard
ENST00000613314.1	Ensembl	ENSP00000481438.1	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
cell-cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252085
Coding exons: 4
Length: 82362
Individuals with no LoFs: 125295
Homozygous LoFs: 1
Heterozygous LoFs: 452
Defined: 125748
p: 0.00180

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.299	559	579	0.965	0.0000389	6016
Missense (PolyPhen)		197	205.3	0.95958		2315
Synonymous	1.04	258	280	0.921	0.0000224	2030
Loss of Function	2.36	14	27.3	0.513	0.00000141	313

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0051	0.0051	notable
Latino/Admixed American	0.00093	0.00093	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00065	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.0019	0.0019	notable
South Asian	0.0033	0.0032	notable
Other	0.0016	0.0016	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: 0.101

Intolerance Scores

LoFtool: 0.625
RVIS EVS: 0.23
RVIS percentile EVS: 68.57

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.459

Gene Damage Prediction

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