PCDHGA8

protein-coding

protocadherin gamma subfamily A, 8, 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]

MANE transcript

NM_032088.2

Inheritance

—

ClinVar variants

U:143B:15

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr5:141,390,157-141,512,975

External References & Databases

Ensembl (ENSG00000253767)

Transcript & Mutation Effects

hg38 • Region Span ~122.8 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 PCDHGA8 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 1196

Inborn genetic diseasesTotal: 104

not providedTotal: 53

Neurodevelopmental disorder with poor growth and skeletal anomaliesTotal: 11

PCDHGC4-related disorderTotal: 5

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

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032088.2. 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				5 clinvar	1 clinvar	6
missense			143 clinvar	8 clinvar	1 clinvar	152
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	143	13	2	158

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_032088.2	RefSeq	NP_114477.1	4	MANE Select
ENST00000398604.3	Ensembl	ENSP00000381605.2	4	MANE Select
NM_014004.3	RefSeq	NP_054723.1	1	Standard
ENST00000610569.1	Ensembl	ENSP00000483161.1	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: ENST00000398604
Coding exons: 4
Length: 120166
Individuals with no LoFs: 102044
Homozygous LoFs: 1502
Heterozygous LoFs: 22154
Defined: 125700
p: 0.0990

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0183	579	580	0.998	0.0000370	6028
Missense (PolyPhen)		173	167.4	1.0335		1871
Synonymous	1.02	250	271	0.921	0.0000201	2007
Loss of Function	0.0947	27	27.5	0.981	0.00000149	311

Population LoF Frequency

Population	CAF	p-value	Status
African	0.18	0.17	notable
Latino/Admixed American	0.15	0.15	notable
Ashkenazi Jewish	0.095	0.093	notable
East Asian	0.11	0.10	notable
Finnish	0.057	0.057	notable
European (Non-Finnish)	0.079	0.079	notable
South Asian	0.12	0.12	notable
Other	0.095	0.093	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: 0.627
RVIS EVS: 0.68
RVIS percentile EVS: 84.77

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	High
Cancer	Medium	Medium	Medium