C2CD3

protein-coding

C2 domain containing 3 centriole elongation regulator, the group of C2 domain containing

Gene summary

This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

MANE transcript

NM_001286577.2

Inheritance

ClinVar variants

P:97U:519B:348

Top phenotype

Craniofacial; Dental; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr11:74,012,718-74,171,210

External References & Databases

Ensembl (ENSG00000168014)

Transcript & Mutation Effects

hg38 • Region Span ~158.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

orofaciodigital syndrome type 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014413

Submitter: G2P

orofaciodigital syndrome type 14SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014413

Submitter: Orphanet

orofaciodigital syndrome type 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014413

Submitter: ClinGen

*C2CD3* was first reported in relation to autosomal recessive orofaciodigital syndrome XIV in 2014 (PMID: 24997988). There's only one disease assertion made for *C2CD3*, therefore a standard curation was completed. Within humans, at least 14 unique variants (deletion, duplication, indel, insertion, single nucleotide) have been reported and more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. The mechanism of pathogenicity is reported to be loss of function whereby biallelic pathogenic variants in the *C2CD3* gene lead to shortening of centrioles and lack of ciliogenesis initiation regulation through centriolar maturation, ciliogenesis protein recruitment, and ciliary vesicle docking. This gene-disease relationship is also supported by animal models (mouse and chick), functional alterations (patient cells), and protein interaction evidence (PMID: 19004860,25053433,27094867,24997988). In summary, there is “Definitive” evidence supporting the relationship between C2CD3 as an AR Ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date May 24, 2023 (SOP Version 9).

orofaciodigital syndrome type 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014413

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Craniofacial; Dental; Genitourinary; Musculoskeletal; Neurologic; OphthalmologicAR

Manifestation: Cardiovascular; Craniofacial; Dental; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

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: 24997988

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C2CD3 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 896

Inborn genetic diseasesTotal: 299

not specifiedTotal: 82

Orofaciodigital syndrome type 14Total: 58

C2CD3-related disorderTotal: 58

Fetal anomalies with a likely genetic causeTotal: 4

Joubert syndromeTotal: 4

C2CD3-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001286577.2. 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			18 clinvar	228 clinvar	12 clinvar	258
missense	2 clinvar	6 clinvar	491 clinvar	90 clinvar	18 clinvar	607
nonsense	17 clinvar	8 clinvar	1 clinvar			26
start loss	1 clinvar	1 clinvar				2
frameshift	31 clinvar	12 clinvar	2 clinvar			45
splice donor/acceptor (+/-2bp)	3 clinvar	16 clinvar	7 clinvar			26
Total	54	43	519	318	30	964

Highest pathogenic variant AF is 0.00016843661

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001286577.2	RefSeq	NP_001273506.1	33	MANE Select
ENST00000334126.12	Ensembl	ENSP00000334379.7	33	MANE Select
NM_015531.6	RefSeq	NP_056346.3	31	Standard
ENST00000313663.11	Ensembl	ENSP00000323339.7	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Anchoring of the basal body to the plasma membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

in utero embryonic development
heart looping
brain development
regulation of smoothened signaling pathway
protein processing

Molecular Function

protein binding

Cellular Component

centrosome
centriole
cytosol
centriolar satellite
ciliary basal body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313663
Coding exons: 31
Length: 158493
Individuals with no LoFs: 125543
Homozygous LoFs: 0
Heterozygous LoFs: 205
Defined: 125748
p: 0.000815

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.535	980	1.03e+3	0.953	0.0000521	12765
Missense (PolyPhen)		289	330.93	0.87329		4270
Synonymous	-0.0496	388	387	1.00	0.0000196	3937
Loss of Function	4.40	46	91.4	0.503	0.00000479	1092

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00082	0.00082	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.00040	0.00039	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the centrioles that acts as a positive regulator of centriole elongation (PubMed:24997988). Promotes assembly of centriolar distal appendage, a structure at the distal end of the mother centriole that acts as an anchor of the cilium, and is required for recruitment of centriolar distal appendages proteins CEP83, SCLT1, CEP89, FBF1 and CEP164. Not required for centriolar satellite integrity or RAB8 activation. Required for primary cilium formation (PubMed:23769972). Required for sonic hedgehog/SHH signaling and for proteolytic processing of GLI3. {ECO:0000269|PubMed:23769972, ECO:0000269|PubMed:24997988}.;
Disease: DISEASE: Orofaciodigital syndrome 14 (OFD14) [MIM:615948]: A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD14 patients show severe microcephaly, cerebral malformations the molar tooth sign, and intellectual disability in addition to canonical OFDS features. {ECO:0000269|PubMed:24997988}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.500
RVIS EVS: 2.18
RVIS percentile EVS: 98.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.140

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High