CDC42

protein-coding

cell division cycle 42, the group of Rho family GTPases

Gene summary

The protein encoded by this gene is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. This protein is highly similar to Saccharomyces cerevisiae Cdc 42, and is able to complement the yeast cdc42-1 mutant. The product of oncogene Dbl was reported to specifically catalyze the dissociation of GDP from this protein. This protein could regulate actin polymerization through its direct binding to Neural Wiskott-Aldrich syndrome protein (N-WASP), which subsequently activates Arp2/3 complex. Alternative splicing of this gene results in multiple transcript variants. Pseudogenes of this gene have been identified on chromosomes 3, 4, 5, 7, 8 and 20. [provided by RefSeq, Apr 2013]

MANE transcript

NM_001791.4

Inheritance

ClinVar variants

P:27U:40B:37

Top phenotype

Takenouchi-Kosaki syndrome

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr1:22,052,627-22,101,360

External References & Databases

Ensembl (ENSG00000070831)

Transcript & Mutation Effects

hg38 • Region Span ~48.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Takenouchi-Kosaki syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014757

Submitter: G2P

Takenouchi-Kosaki syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014757

Submitter: Labcorp Genetics (formerly Invitae)

Takenouchi-Kosaki syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014757

Submitter: ClinGen

CDC42 was first reported in relation to autosomal dominant macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome (sometimes known as Takenouchi-Kosaki syndrome) in 2015 (Takenouchi T, et al., 2015, PMID: 26386261). CDC42, a master regulator of actin cytoskeleton and major node in intracellular signaling, is associated with a heterogeneous set of developmental and multi-system phenotypes, demonstrating the critical requirement of proper CDC42 function in a large array of developmental processes. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Patients have a broad spectrum of anomalies; core clinical features include defective growth, intellectual disability, facial dysmorphism, hearing/vision problems, cardiac malformations, immune, hematologic, and lymphatic abnormalities, and brain malformations. Nine unique missense variants have been reported in this gene in at least 9 probands in 2 publications (PMIDs: 26386261 and 29394990). Segregation was observed in one family (Family 30153 in PMID: 29394990), all others were de novo occurrences. This gene-disease relationship is supported by its interaction with WAS (PMID: 8643625) and multiple model systems with partial recapitulation of human disease (PMIDs: 29394990, 16510873, 20139097, 22387309). In summary CDC42 is definitively associated with autosomal dominant macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome.

Takenouchi-Kosaki syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014757

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Takenouchi-Kosaki syndromeAD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 26386261; 26708094; 29394990

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDC42 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 128

Takenouchi-Kosaki syndromeTotal: 22

not specifiedTotal: 18

Postnatal growth retardationTotal: 9

Abnormality of the immune systemTotal: 9

CDC42-related disorderTotal: 9

Abnormality of blood and blood-forming tissuesTotal: 9

Abnormal facial shapeTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001791.4. 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			1 clinvar	34 clinvar	3 clinvar	38
missense	10 clinvar	16 clinvar	36 clinvar			62
nonsense						0
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	10	17	40	34	3	104

Highest pathogenic variant AF is 0.0000013762314

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001791.4	RefSeq	NP_001782.1	5	MANE Select
ENST00000656825.1	Ensembl	ENSP00000499457.1	5	MANE Select
NM_001039802.2	RefSeq	NP_001034891.1	5	Standard
NM_044472.3	RefSeq	NP_426359.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cdc42	Danio rerio	Structure: photoreceptor cell Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

cdc42

Danio rerio

Structure: photoreceptor cell

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Focal adhesion - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Renal cell carcinoma - Homo sapiens (human)

Biological Process

sprouting angiogenesis
protein phosphorylation
endocytosis
phagocytosis, engulfment
actin filament organization

Molecular Function

GTPase activity
protein serine/threonine kinase activity
protein binding
GTP binding
protein kinase binding

Cellular Component

Golgi membrane
cytoplasm
endoplasmic reticulum membrane
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000344548
Coding exons: 5
Length: 40318
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125679
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.04	17	104	0.163	0.00000544	1229
Missense (PolyPhen)		1	29.982	0.033353		378
Synonymous	-0.608	45	40.1	1.12	0.00000222	388
Loss of Function	2.55	1	9.47	0.106	4.99e-7	115

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase. Plays a role in the extension and maintenance of the formation of thin, actin-rich surface projections called filopodia. Mediates CDC42-dependent cell migration. Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. Facilitates filopodia formation upon DOCK11-activation (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups. {ECO:0000250|UniProtKB:P60766, ECO:0000269|PubMed:14978216, ECO:0000269|PubMed:15642749, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:26465210}.;
Disease: DISEASE: Takenouchi-Kosaki syndrome (TKS) [MIM:616737]: A syndrome characterized by macrothrombocytopenia, lymphedema, mental retardation, developmental delay, and distinctive facial features. {ECO:0000269|PubMed:26386261, ECO:0000269|PubMed:26708094}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.914

Intolerance Scores

LoFtool: 0.282
RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.926

Gene Damage Prediction

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