PCDHGA2

protein-coding

protocadherin gamma subfamily A, 2, 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_018915.4

Inheritance

—

ClinVar variants

U:129B:17

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr5:141,338,760-141,512,975

External References & Databases

Ensembl (ENSG00000081853)

Transcript & Mutation Effects

hg38 • Region Span ~174.2 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 PCDHGA2 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 2537

Inborn genetic diseasesTotal: 104

not providedTotal: 77

Neurodevelopmental disorder with poor growth and skeletal anomaliesTotal: 11

PCDHGC4-related disorderTotal: 5

EBV-positive nodal T- and NK-cell lymphomaTotal: 4

Neurodevelopmental disorderTotal: 1

Complex neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018915.4. 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				6 clinvar	1 clinvar	7
missense			127 clinvar	10 clinvar		137
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	129	16	1	146

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_018915.4	RefSeq	NP_061738.1	4	MANE Select
ENST00000394576.3	Ensembl	ENSP00000378077.2	4	MANE Select
NM_032009.3	RefSeq	NP_114398.1	1	Standard
ENST00000528330.2	Ensembl	ENSP00000483020.1	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: ENST00000394576
Coding exons: 4
Length: 174008
Individuals with no LoFs: 125601
Homozygous LoFs: 0
Heterozygous LoFs: 147
Defined: 125748
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.145	580	570	1.02	0.0000391	6016
Missense (PolyPhen)		217	213.93	1.0144		2503
Synonymous	-0.0112	270	270	1.00	0.0000220	2025
Loss of Function	0.454	25	27.6	0.907	0.00000159	308

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00071	0.00071	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00059	0.00059	rare
South Asian	0.00072	0.00065	rare
Other	0.00065	0.00065	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.;

Intolerance Scores

LoFtool: 0.904
RVIS EVS: 0.28
RVIS percentile EVS: 70.78

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