CC2D2A

protein-coding

coiled-coil and C2 domain containing 2A, the group of MKS complex

Gene summary

This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

MANE transcript

NM_001378615.1

Inheritance

ClinVar variants

P:365U:744B:591

Top phenotype

COACH syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr4:15,469,865-15,601,552

External References & Databases

Ensembl (ENSG00000048342)

Transcript & Mutation Effects

hg38 • Region Span ~131.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome with oculorenal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

Joubert syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012849

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 93STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030797

Submitter: Labcorp Genetics (formerly Invitae)

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012849

Submitter: Genomics England PanelApp

COACH syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008996

Submitter: Orphanet

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*CC2D2A* (OMIM:612013) encodes for coiled-coil and C2 domain-containing protein 2A (CC2D2A), which localizes to the ciliary transition zone of the cilium (PMID:18950740). *CC2D2A* has been associated with the following autosomal-recessive disease entities: COACH syndrome 2 (OMIM:61911), Joubert syndrome 9 (OMIM:612285), Meckel syndrome 6 (OMIM:612284), and Retinitis pigmentosa 93 (OMIM:619845). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. While these disease entities represent a wide range of clinical severity, the molecular mechanism is loss of function, and all disease entities have autosomal-recessive inheritance. Therefore, the above disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). Pathogenic variants in *CC2D2A* were curated from nine affected probands with *CC2D2A*-ciliopathies from five different publications (PMID:18387594; PMID:18950740, PMID:18513680, PMID:19777577, PMID:19574260). Five of the curated probands were characterized by Joubert syndrome 9 (OMIM:612285) or COACH syndrome 2 (OMIM:61911); and four of the affected probands had Meckel syndrome 6 (OMIM:612284). Eight predicted protein-truncating variants and three missense variants were curated for a total of eleven unique variants. There are many more cases and variants described in detail in the literature (PMID:33486889), but the maximum of 12 points was reached. The mechanism of disease in all curated cases is homozygous or compound-heterozygous loss of function (PMID:18950740). In ciliopathy-causing genes, disruption to ciliary biogenesis is an established disease mechanism. CC2D2A localizes to the ciliary transition zone and plays a critical role in cilia formation, an established molecular function for known ciliopathy-causing gene products (PMID:24947469). CC2D2A physically interacts and co-localizes with CEP290, the protein product of a gene known to cause multiple hereditary ciliopathies with similar organ involvement and pleiotropy (OMIM:610142). In fibroblasts derived from a patient with Meckel syndrome (homozygous *CC2D2A* p.Gln588Ter), cilia were notably absent (PMID:18513680). The *Cc2d2a* knockout mouse model is embryonically lethal and demonstrates pleiotropic organogenesis defects that recapitulate the Meckel syndrome phenotype in humans (PMID:21725307; PMID:24947469). Cilia are absent from many tissues, including the embryonic node, perinatal kidney tubules, and the developing neural tube, where Shh signaling is consequently disrupted. (PMID:24947469). Primary cilium biogenesis defects observed in *Cc2d2a* loss-of-function mouse embryonic fibroblasts (MEFs) are consistent with the disease mechanism in humans, where loss and/or abnormal cilia morphology have been observed (PMID:24947469). In summary, there is definitive evidence to support the relationship between *CC2D2A* and autosomal recessive ciliopathy-*CC2D2A*. The molecular mechanism is loss of function, leading to defects in ciliary formation and function. 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 08/24/2022 (SOP Version 9).

Joubert syndrome 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012849

Submitter: G2P

Clinical Genomic Database (CGD)

COACH syndrome 2AR

Manifestation: Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary; Renal

Intervention: Gastrointestinal

Rationale: In COACH syndrome, among other findings, individuals may have hepatic disease, and it has been suggested that identification of liver disease is critical as some patients may develop complications such as portal hypertension with fatal variceal bleeding

Comments: Digenic inheritance has been reported

Refs: 18950740; 18387594; 18513680; 20301500; 20671153; 22246503; 22241855; 30267408

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CC2D2A variants in ClinVar

39 Conditions Cataloged

Meckel-Gruber syndromeTotal: 1808

Joubert syndromeTotal: 1806

not providedTotal: 476

Joubert syndrome 9Total: 418

Meckel syndrome, type 6Total: 392

Retinitis pigmentosa 93Total: 269

COACH syndrome 2Total: 268

Inborn genetic diseasesTotal: 237

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378615.1. 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		3 clinvar	21 clinvar	503 clinvar	2 clinvar	529
missense	11 clinvar	55 clinvar	708 clinvar	82 clinvar	3 clinvar	859
nonsense	67 clinvar	30 clinvar	3 clinvar			100
start loss						0
frameshift	77 clinvar	50 clinvar	4 clinvar			131
splice donor/acceptor (+/-2bp)	15 clinvar	57 clinvar	8 clinvar	1 clinvar		81
Total	170	195	744	586	5	1700

Highest pathogenic variant AF is 0.00030257885

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378615.1	RefSeq	NP_001365544.1	36	MANE Select
ENST00000424120.6	Ensembl	ENSP00000403465.1	36	MANE Select
NM_001080522.2	RefSeq	NP_001073991.2	36	Standard
NM_001164720.3	RefSeq	NP_001158192.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cc2d2a	Danio rerio	Structure: retinal rod cell Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

cc2d2a

Danio rerio

Structure: retinal rod cell

Quality: malformed

abnormal

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

neural tube closure
smoothened signaling pathway
determination of left/right symmetry
heart development
axoneme assembly

Cellular Component

cytosol
cytoskeleton
ciliary transition zone
MKS complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000424120
Coding exons: 36
Length: 131692
Individuals with no LoFs: 124425
Homozygous LoFs: 1
Heterozygous LoFs: 311
Defined: 124737
p: 0.00125

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.647	758	810	0.936	0.0000439	10538
Missense (PolyPhen)		131	172.23	0.76062		2239
Synonymous	0.548	280	292	0.959	0.0000156	3034
Loss of Function	3.32	58	92.4	0.627	0.00000552	1099

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0015	notable
Latino/Admixed American	0.0010	0.00096	notable
Ashkenazi Jewish	0.0023	0.0023	notable
East Asian	0.00045	0.00044	rare
Finnish	0.0033	0.0033	notable
European (Non-Finnish)	0.0010	0.00096	notable
South Asian	0.0013	0.0012	notable
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity). {ECO:0000250, ECO:0000269|PubMed:18513680}.;
Disease: DISEASE: Meckel syndrome 6 (MKS6) [MIM:612284]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:18513680, ECO:0000269|PubMed:19466712, ECO:0000269|PubMed:24706459}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 9 (JBTS9) [MIM:612285]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:18387594, ECO:0000269|PubMed:18950740, ECO:0000269|PubMed:19777577, ECO:0000269|PubMed:22241855, ECO:0000269|PubMed:22246503, ECO:0000269|PubMed:22425360, ECO:0000269|PubMed:23012439, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: COACH syndrome (COACHS) [MIM:216360]: A disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome and related disorders. Other features, such as coloboma and renal cysts, may be variable. {ECO:0000269|PubMed:19574260}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.546
RVIS EVS: -0.92
RVIS percentile EVS: 9.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.0924

Gene Damage Prediction

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