PCDHGC4

protein-coding

protocadherin gamma subfamily C, 4, 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_018928.3

Inheritance

ClinVar variants

P:11U:110B:17

Top phenotype

Neurodevelopmental disorder with poor growth and skeletal anomalies

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr5:141,484,997-141,512,975

External References & Databases

Ensembl (ENSG00000242419)

Transcript & Mutation Effects

hg38 • Region Span ~28.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with poor growth and skeletal anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859252

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with poor growth and skeletal anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859252

Submitter: PanelApp Australia

neurodevelopmental disorder with poor growth and skeletal anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859252

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with poor growth and skeletal anomaliesAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 34244665

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDHGC4 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 113

Inborn genetic diseasesTotal: 104

not providedTotal: 23

Neurodevelopmental disorder with poor growth and skeletal anomaliesTotal: 11

PCDHGC4-related disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018928.3. 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			1 clinvar	11 clinvar	1 clinvar	13
missense	1 clinvar	1 clinvar	108 clinvar	5 clinvar		115
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss						0
frameshift	2 clinvar	3 clinvar				5
splice donor/acceptor (+/-2bp)						0
Total	5	6	110	16	1	138

Highest pathogenic variant AF is 0.0000043382875

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018928.3	RefSeq	NP_061751.1	4	MANE Select
ENST00000306593.2	Ensembl	ENSP00000306918.1	4	MANE Select
NM_001386884.1	RefSeq	NP_001373813.1	4	Standard
NM_032406.1	RefSeq	NP_115782.1	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
synapse organization

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: ENST00000306593
Coding exons: 4
Length: 27806
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.97	422	552	0.764	0.0000320	6053
Missense (PolyPhen)		76	148.13	0.51306		1768
Synonymous	2.15	187	228	0.819	0.0000132	2080
Loss of Function	4.36	4	29.6	0.135	0.00000193	293

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

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: 0.176
RVIS EVS: -0.53
RVIS percentile EVS: 20.82

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