CC2D2A

Summary

CC2D2A (coiled-coil and C2 domain containing 2A, HGNC:29253) is a protein-coding gene on chromosome 4p15.32, encoding Coiled-coil and C2 domain-containing protein 2A (Q9P2K1). 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.

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.

Source: NCBI Gene 57545 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 2,374 total — 181 pathogenic, 109 likely-pathogenic
• Phenotypes (HPO): 158
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001378615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29253
Approved symbol	CC2D2A
Name	coiled-coil and C2 domain containing 2A
Location	4p15.32
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1345, MKS6, JBTS9
Ensembl gene	ENSG00000048342
Ensembl biotype	protein_coding
OMIM	612013
Entrez	57545

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 17 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000389652, ENST00000424120, ENST00000503292, ENST00000503658, ENST00000506643, ENST00000507954, ENST00000510220, ENST00000511544, ENST00000512202, ENST00000512702, ENST00000513035, ENST00000513811, ENST00000514039, ENST00000514450, ENST00000515124, ENST00000634028, ENST00000650860, ENST00000651385, ENST00000652443, ENST00000674945, ENST00000675619, ENST00000675768, ENST00000676337, ENST00000680586, ENST00000860661, ENST00000860662, ENST00000951218, ENST00000951219

RefSeq mRNA: 5 — MANE Select: NM_001378615 NM_001080522, NM_001164720, NM_001378615, NM_001378617, NM_020785

CCDS: CCDS47026, CCDS47027, CCDS54744, CCDS93481

Canonical transcript exons

ENST00000424120 — 37 exons

Exon	Start	End
ENSE00000705658	15559165	15559257
ENSE00000705702	15557304	15557507
ENSE00000705774	15550824	15550980
ENSE00001506462	15596085	15596207
ENSE00001506463	15589545	15589679
ENSE00001506465	15587816	15587929
ENSE00001506466	15586157	15586246
ENSE00001506468	15579968	15580171
ENSE00001506471	15570398	15570496
ENSE00001506472	15569293	15569389
ENSE00001506473	15567677	15567786
ENSE00001506475	15567377	15567482
ENSE00001506476	15563355	15563522
ENSE00001506477	15560531	15560622
ENSE00001731775	15574150	15574326
ENSE00002043164	15469882	15470057
ENSE00003460779	15597407	15597465
ENSE00003480176	15516625	15516756
ENSE00003498945	15502429	15502517
ENSE00003506220	15514707	15514869
ENSE00003509973	15511247	15511423
ENSE00003512227	15478723	15478806
ENSE00003538646	15480704	15480827
ENSE00003539467	15599529	15599706
ENSE00003541542	15540837	15541014
ENSE00003555581	15515868	15516004
ENSE00003565843	15527447	15527656
ENSE00003574573	15502822	15502923
ENSE00003585677	15553158	15553305
ENSE00003589994	15533193	15533333
ENSE00003596061	15528620	15528726
ENSE00003627755	15537899	15538137
ENSE00003659492	15555072	15555210
ENSE00003661073	15475915	15475971
ENSE00003681774	15510139	15510240
ENSE00003776346	15601237	15601552
ENSE00003786707	15536920	15537076

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 96.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.0809 / max 161.6740, expressed in 1558 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46984	8.4637	1428
46982	5.9172	1276
46985	0.4938	302
46983	0.2062	76

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.49	gold quality
bronchial epithelial cell	CL:0002328	96.23	gold quality
bronchus	UBERON:0002185	95.11	gold quality
ventricular zone	UBERON:0003053	93.15	gold quality
calcaneal tendon	UBERON:0003701	92.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.18	gold quality
colonic epithelium	UBERON:0000397	90.16	gold quality
sural nerve	UBERON:0015488	89.71	gold quality
right coronary artery	UBERON:0001625	89.67	gold quality
ganglionic eminence	UBERON:0004023	89.55	gold quality
tendon	UBERON:0000043	89.53	gold quality
adrenal tissue	UBERON:0018303	89.12	gold quality
popliteal artery	UBERON:0002250	88.82	gold quality
tibial artery	UBERON:0007610	88.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.45	gold quality
fallopian tube	UBERON:0003889	88.14	gold quality
aorta	UBERON:0000947	88.03	gold quality
left coronary artery	UBERON:0001626	88.02	gold quality
endocervix	UBERON:0000458	87.70	gold quality
pancreatic ductal cell	CL:0002079	87.63	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	87.45	gold quality
ascending aorta	UBERON:0001496	87.33	gold quality
thoracic aorta	UBERON:0001515	87.27	gold quality
descending thoracic aorta	UBERON:0002345	87.22	gold quality
stromal cell of endometrium	CL:0002255	87.14	gold quality
coronary artery	UBERON:0001621	86.89	gold quality
kidney epithelium	UBERON:0004819	86.84	gold quality
smooth muscle tissue	UBERON:0001135	86.64	gold quality
body of uterus	UBERON:0009853	86.25	gold quality
adenohypophysis	UBERON:0002196	86.23	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2251.03
E-MTAB-11121	yes	881.02
E-MTAB-7316	yes	27.31
E-ANND-3	yes	8.62
E-MTAB-9388	yes	6.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting CC2D2A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-192-3P	97.52	67.66	1001
HSA-MIR-4280	96.44	67.69	473

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• A homozygous splice-site mutation segregating in the family with autosomal-recessive mental retardation, within a coiled-coil and C2 domain-containing gene, CC2D2A was identified. (PMID:18387594)
• CC2D2A appears to have at least two cilia-related functions: the molecule seems to be a part of the basal body complex where the cilium is assembled from and also seems to act as a sensor for the intracellular calcium. (PMID:18513680)
• CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. (PMID:18950740)
• CC2D2A causes autosomal-recessive mental retardation with retinitis pigmentosa. (PMID:19068953)
• Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L. (PMID:19574260)
• Mutations within the CC2D2A gene are associated with Meckel and Joubert syndromes. (PMID:19777577)
• Results suggest the involvement of CC2D1A and CC2D2A in mental retardation in the Han Chinese population, and some specific haplotypes may be susceptible or protective. (PMID:22023432)
• CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures. (PMID:22241855)
• these data support a model where CC2D2A associates with NINL to provide a docking point for cilia-directed cargo vesicles, suggesting a mechanism by which transition zone proteins can control the protein content of the ciliary compartment. (PMID:26485645)
• Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in Saudi Arabian cohort. (PMID:26862157)
• Using a dedicated bioinformatics algorithm for TE detection, we identified an exonic retrotransposon insertion of L1 to the CC2D2A locus in a patient with Meckel-Gruber syndrome, the most severe form of the ciliopathy phenotypes. (PMID:28374938)
• Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes. (PMID:30267408)
• Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants. (PMID:31577543)
• Primary cilia biogenesis and associated retinal ciliopathies. (PMID:32747192)
• Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family. (PMID:32989887)
• Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies. (PMID:33486889)
• New insights into CC2D2A-related Joubert syndrome. (PMID:36319078)
• Exome Analysis Reveals Novel Missense and Deletion Variants in the CC2D2A Gene as Causative of Joubert Syndrome. (PMID:37107568)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cc2d2a	ENSDARG00000090971
mus_musculus	Cc2d2a	ENSMUSG00000039765
rattus_norvegicus	Cc2d2a	ENSRNOG00000059715
drosophila_melanogaster	Cc2d2a	FBGN0263113
caenorhabditis_elegans	mks-6	WBGENE00010642

Paralogs (2): CEP76 (ENSG00000101624), CC2D2B (ENSG00000188649)

Protein

Protein identifiers

Coiled-coil and C2 domain-containing protein 2A — Q9P2K1 (reviewed: Q9P2K1)

All UniProt accessions (11): A0A0J9YXT3, A0A0J9YY35, A0A0M3HER0, A0A140T8Y7, A0A494C0X1, A0A494C1C5, A0A6Q8PG12, Q9P2K1, A0A6Q8PHJ7, D6R9V3, H0Y941

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Part of the tectonic-like complex (also named B9 complex).

Subcellular location. Cytoplasm. Cytoskeleton. Cilium basal body.

Tissue specificity. Strongly expressed in prostate, pancreas, kidney, lung, liver, retina, kidney, fetal brain and fetal kidney. Lower expression in spleen, small intestine, colon, skeletal muscle, ovary, thymus and heart.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. COACH syndrome 2 (COACH2) [MIM:619111] A form of COACH syndrome, a disorder characterized by cerebellar vermis hypoplasia, developmental delay, impaired intellectual development, ataxia, 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. COACH2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 93 (RP93) [MIM:619845] A form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. RP93 is an autosomal recessive, mild to moderate form, with onset in the second or third decade of life. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P2K1-4	1	yes
Q9P2K1-2	2
Q9P2K1-5	3
Q9P2K1-6	4

RefSeq proteins (5): NP_001073991, NP_001158192, NP_001365544, NP_001365546, NP_065836 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR028928	CC2D2AN-C2	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR041510	DUF5523	Domain
IPR052434	Tectonic-like_complex_comp	Family
IPR056288	CEP76_C	Domain
IPR056290	CEPT76/DRC7_peptidase-like_dom	Domain

Pfam: PF15625, PF17661, PF24652, PF24656

UniProt features (51 total): sequence variant 31, compositionally biased region 6, splice variant 6, region of interest 3, coiled-coil region 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2K1-F1	69.46	0.13

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly

MSigDB gene sets: 420 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, MODULE_503, GOBP_SPECIFICATION_OF_SYMMETRY, MODULE_205, MODULE_195, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_CILIUM_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_MICROTUBULE_BUNDLE_FORMATION

GO Biological Process (13): kidney development (GO:0001822), neural tube closure (GO:0001843), smoothened signaling pathway (GO:0007224), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), axoneme assembly (GO:0035082), camera-type eye development (GO:0043010), motile cilium assembly (GO:0044458), cilium assembly (GO:0060271), protein localization to ciliary transition zone (GO:1904491), non-motile cilium assembly (GO:1905515), embryonic brain development (GO:1990403), cell projection organization (GO:0030030)

GO Molecular Function (0):

GO Cellular Component (7): cytosol (GO:0005829), ciliary transition zone (GO:0035869), MKS complex (GO:0036038), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Assembly of the 9+0 primary cilium	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cilium assembly	3
animal organ development	2
protein localization to cilium	2
renal system development	1
primary neural tube formation	1
tube closure	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
circulatory system development	1
microtubule bundle formation	1
cellular component assembly	1
eye development	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
embryonic organ development	1
cellular component organization	1
cytoplasm	1
cilium	1
protein-containing complex	1
ciliary transition zone	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CC2D2A	TMEM67	Q5HYA8	990
CC2D2A	B9D1	Q9UPM9	989
CC2D2A	TMEM216	Q9P0N5	988
CC2D2A	CEP290	O15078	983
CC2D2A	MKS1	Q9NXB0	982
CC2D2A	TCTN1	Q2MV58	981
CC2D2A	AHI1	Q8N157	978
CC2D2A	TCTN2	Q96GX1	974
CC2D2A	B9D2	Q9BPU9	969
CC2D2A	RPGRIP1L	Q68CZ1	969
CC2D2A	TCTN3	Q6NUS6	968
CC2D2A	TMEM231	Q9H6L2	953
CC2D2A	NPHP1	O15259	948
CC2D2A	ARL13B	Q3SXY8	933
CC2D2A	TMEM237	Q96Q45	872

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TCTN2	TCTN3	psi-mi:“MI:0914”(association)	0.640
CC2D2A	OFD1	psi-mi:“MI:0914”(association)	0.420
CC2D2A	OFD1	psi-mi:“MI:2364”(proximity)	0.420
B9D2	PARN	psi-mi:“MI:0914”(association)	0.350
TCTN1	NPTX1	psi-mi:“MI:0914”(association)	0.350
TMEM231	WFS1	psi-mi:“MI:0914”(association)	0.350
TCTN1	GUSB	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): OFD1 (Affinity Capture-Western), PCM1 (Affinity Capture-Western), AHI1 (Proximity Label-MS), ASCC2 (Proximity Label-MS), ASCC3 (Proximity Label-MS), CEP131 (Proximity Label-MS), B9D1 (Proximity Label-MS), B9D2 (Proximity Label-MS), DVL3 (Proximity Label-MS), ECH1 (Proximity Label-MS), GPATCH1 (Proximity Label-MS), HAUS8 (Proximity Label-MS), LMNA (Proximity Label-MS), MB21D2 (Proximity Label-MS), MKS1 (Proximity Label-MS)

ESM2 similar proteins: A0A087WRI3, A2BFC9, A2RRW4, A4QMS7, A6NJV1, A6NL82, A6QPC0, A6QQ68, A8E4X8, A8E5W8, A8QW39, A9JS51, D6REC4, F1P3Y5, G3X6E2, P0C875, Q0VB26, Q1MSJ5, Q2IA00, Q2T9Q3, Q2TA11, Q3UY96, Q494V2, Q497Q6, Q4KKZ1, Q4QR77, Q4R5Y0, Q4R8V8, Q5NC57, Q5ZIH9, Q6J272, Q6PII3, Q6ZQR2, Q6ZVS7, Q7Z4T9, Q8CFW7, Q8N1D5, Q8N6G2, Q8WW14, Q95LR0

Diamond homologs: Q6DHV5, Q8CFW7, Q95K30, Q9P2K1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 10 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	6	44.1×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

2374 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	181
Likely pathogenic	109
Uncertain significance	779
Likely benign	944
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1049636	NM_001378615.1(CC2D2A):c.248-2A>T	Pathogenic
1068683	NM_001378615.1(CC2D2A):c.4086del (p.Asp1364fs)	Pathogenic
1069485	NM_001378615.1(CC2D2A):c.3376G>A (p.Glu1126Lys)	Pathogenic
1070038	NM_001378615.1(CC2D2A):c.1297del (p.Gln433fs)	Pathogenic
1071905	NM_001378615.1(CC2D2A):c.4256del (p.Gly1419fs)	Pathogenic
1073574	NM_001378615.1(CC2D2A):c.2898_2899dup (p.Ile967fs)	Pathogenic
1074596	NM_001378615.1(CC2D2A):c.1538G>A (p.Trp513Ter)	Pathogenic
1074828	NM_001378615.1(CC2D2A):c.2875del (p.Glu959fs)	Pathogenic
1075055	NM_001378615.1(CC2D2A):c.418_419insGAGGGAGGAGCCAAGATGGCCGAATAGGAACAGCTCCGGTCTACAGCTCCCAGCGTGAGCGACGCAGAAGACGGTGATTTCTGCATCTCCATCTGAGGTACCGGGTTCATNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAAGAATTGG (p.Glu140delinsGlyGlyArgSerGlnAspGlyArgIleGlyThrAlaProValTyrSerSerGlnArgGluArgArgArgArgArgTer)	Pathogenic
1076226	NC_000004.11:g.(?15480341)(15482457_?)del	Pathogenic
1076327	NM_001378615.1(CC2D2A):c.3320_3321del (p.Phe1107fs)	Pathogenic
1322033	NM_001378615.1(CC2D2A):c.2625+2T>C	Pathogenic
1334771	NM_001378615.1(CC2D2A):c.3626del (p.Pro1209fs)	Pathogenic
1354891	NM_001378615.1(CC2D2A):c.4460dup (p.Ser1488fs)	Pathogenic
1357393	NM_001378615.1(CC2D2A):c.3311A>G (p.Glu1104Gly)	Pathogenic
1367697	NM_001378615.1(CC2D2A):c.3640_3643dup (p.Ser1215fs)	Pathogenic
1395827	NM_001378615.1(CC2D2A):c.3688C>T (p.Arg1230Ter)	Pathogenic
1401321	NM_001378615.1(CC2D2A):c.948del (p.Gly317_Val318insTer)	Pathogenic
1423048	NM_001378615.1(CC2D2A):c.3810_3811del (p.Lys1272fs)	Pathogenic
1444655	NM_001378615.1(CC2D2A):c.3803_3804del (p.Gln1268fs)	Pathogenic
1686896	NC_000004.12:g.15563877_15580021del	Pathogenic
1686898	NM_001378615.1(CC2D2A):c.4730_4731delinsTGTATA (p.Ala1577fs)	Pathogenic
1805718	NM_001378615.1(CC2D2A):c.2710G>T (p.Glu904Ter)	Pathogenic
1806266	NM_001378615.1(CC2D2A):c.2164G>T (p.Glu722Ter)	Pathogenic
191188	NM_001378615.1(CC2D2A):c.4437+1G>A	Pathogenic
1930499	NM_001378615.1(CC2D2A):c.4229G>A (p.Trp1410Ter)	Pathogenic
193831	NM_001080522.2(CC2D2A):c.1017dup (p.Glu340Argfs)	Pathogenic
1957318	NM_001378615.1(CC2D2A):c.4465G>C (p.Asp1489His)	Pathogenic
2016927	NM_001378615.1(CC2D2A):c.4569T>A (p.Cys1523Ter)	Pathogenic
2025640	NM_001378615.1(CC2D2A):c.3820C>T (p.Gln1274Ter)	Pathogenic

SpliceAI

6070 predictions. Top by Δscore:

Variant	Effect	Δscore
4:15478711:A:AG	acceptor_gain	1.0000
4:15478712:T:G	acceptor_gain	1.0000
4:15478717:A:AG	acceptor_gain	1.0000
4:15478718:C:G	acceptor_gain	1.0000
4:15478719:A:AG	acceptor_gain	1.0000
4:15478719:AAAG:A	acceptor_gain	1.0000
4:15478720:A:G	acceptor_gain	1.0000
4:15478803:ACAGG:A	donor_loss	1.0000
4:15478805:AGG:A	donor_loss	1.0000
4:15478806:GGT:G	donor_loss	1.0000
4:15478807:G:GA	donor_loss	1.0000
4:15478808:T:A	donor_loss	1.0000
4:15480823:ACGGA:A	donor_gain	1.0000
4:15480824:CGGA:C	donor_gain	1.0000
4:15480824:CGGAG:C	donor_loss	1.0000
4:15480825:GGA:G	donor_gain	1.0000
4:15480825:GGAG:G	donor_gain	1.0000
4:15480826:GA:G	donor_gain	1.0000
4:15480826:GAG:G	donor_gain	1.0000
4:15480826:GAGT:G	donor_loss	1.0000
4:15480827:AGTA:A	donor_loss	1.0000
4:15480828:G:GG	donor_gain	1.0000
4:15480829:TAAGT:T	donor_loss	1.0000
4:15511407:G:GT	donor_gain	1.0000
4:15511418:G:GT	donor_gain	1.0000
4:15514695:A:AG	acceptor_gain	1.0000
4:15514696:A:AG	acceptor_gain	1.0000
4:15514697:C:G	acceptor_gain	1.0000
4:15514698:A:AG	acceptor_gain	1.0000
4:15514698:ATTAT:A	acceptor_gain	1.0000

AlphaMissense

10666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:15553238:T:A	W807R	0.999
4:15553238:T:C	W807R	0.999
4:15567758:T:A	W1124R	0.999
4:15567758:T:C	W1124R	0.999
4:15599587:T:A	W1519R	0.999
4:15599587:T:C	W1519R	0.999
4:15527561:A:C	S422R	0.997
4:15527563:C:A	S422R	0.997
4:15527563:C:G	S422R	0.997
4:15540851:G:C	R673T	0.997
4:15540852:A:C	R673S	0.997
4:15540852:A:T	R673S	0.997
4:15563489:C:A	A1050D	0.997
4:15596154:T:A	W1462R	0.997
4:15596154:T:C	W1462R	0.997
4:15601244:G:A	G1561E	0.997
4:15601343:C:A	A1594D	0.997
4:15553240:G:C	W807C	0.996
4:15553240:G:T	W807C	0.996
4:15555147:G:C	W854C	0.996
4:15555147:G:T	W854C	0.996
4:15563488:G:C	A1050P	0.996
4:15567760:G:C	W1124C	0.996
4:15567760:G:T	W1124C	0.996
4:15570453:G:A	G1184E	0.996
4:15601342:G:C	A1594P	0.996
4:15601390:T:A	W1610R	0.996
4:15601390:T:C	W1610R	0.996
4:15527574:T:A	V426D	0.995
4:15550933:T:C	F764S	0.995

dbSNP variants (sampled 300 via entrez): RS1000013603 (4:15472546 A>G), RS10000250 (4:15480853 A>C,G,T), RS1000028504 (4:15539223 C>T), RS1000076869 (4:15517169 G>A,C), RS1000101333 (4:15572375 A>G,T), RS1000156867 (4:15571809 A>C,T), RS1000169301 (4:15530470 T>C), RS1000180058 (4:15485746 C>G,T), RS1000248164 (4:15479372 G>T), RS1000252577 (4:15577986 C>A,T), RS1000253014 (4:15545673 C>CA), RS1000259860 (4:15517353 C>T), RS1000273144 (4:15525325 G>A), RS10002934 (4:15578816 G>A,C,T), RS1000296231 (4:15486108 T>C)

Disease associations

OMIM: gene MIM:612013 | disease phenotypes: MIM:213300, MIM:249000, MIM:612284, MIM:612285, MIM:619845, MIM:619111, MIM:216360, MIM:206500, MIM:603596, MIM:119800, MIM:174200, MIM:173900, MIM:300804, MIM:256100

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 9	Definitive	Autosomal recessive
retinitis pigmentosa 93	Strong	Autosomal recessive
COACH syndrome 1	Supportive	Autosomal recessive
Joubert syndrome with oculorenal defect	Supportive	Autosomal recessive
Meckel syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy	Definitive	AR

Mondo (28): Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921), Meckel syndrome, type 6 (MONDO:0012848), Joubert syndrome 9 (MONDO:0012849), retinitis pigmentosa 93 (MONDO:0030797), COACH syndrome 2 (MONDO:0030859), COACH syndrome 1 (MONDO:0800103), anencephaly (MONDO:0000819), cystic kidney disease (MONDO:0002473), polydactyly (MONDO:0021003), Joubert syndrome 1 (MONDO:0008944), inherited retinal dystrophy (MONDO:0019118), Joubert syndrome and related disorders (MONDO:0015369), ciliopathy (MONDO:0005308), neurodevelopmental disorder (MONDO:0700092)

Orphanet (12): Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), Joubert syndrome with oculorenal defect (Orphanet:2318), Joubert syndrome with hepatic defect (Orphanet:1454), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Joubert syndrome and related disorders (Orphanet:140874), Ciliopathy (Orphanet:363250), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Pituitary stalk interruption syndrome (Orphanet:95496), Orofaciodigital syndrome type 6 (Orphanet:2754), Nephronophthisis (Orphanet:655), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

158 total (30 of 158 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000037	Male pseudohermaphroditism
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000073	Ureteral duplication
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000221	Furrowed tongue
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000457	Depressed nasal ridge

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000714_9	Conduct disorder	8.000000e-06
GCST001762_631	Obesity-related traits	6.000000e-06
GCST003998_24	Joint mobility (Beighton score)	7.000000e-07
GCST004601_53	Red blood cell count	3.000000e-09
GCST004602_145	Mean corpuscular volume	8.000000e-20
GCST004630_135	Mean corpuscular hemoglobin	3.000000e-18
GCST005023_21	Initial pursuit acceleration	9.000000e-06
GCST005023_6	Initial pursuit acceleration	6.000000e-06
GCST006011_103	Mean corpuscular volume	9.000000e-11
GCST007325_175	General risk tolerance (MTAG)	1.000000e-08
GCST90002390_202	Mean corpuscular hemoglobin	7.000000e-46
GCST90002392_646	Mean corpuscular volume	4.000000e-48
GCST90002396_266	Mean reticulocyte volume	3.000000e-14
GCST90002397_2	Mean spheric corpuscular volume	4.000000e-25

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007905	joint hypermobility measurement
EFO:0004305	erythrocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0008434	initial pursuit acceleration
EFO:0008579	risk-taking behaviour
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D000757	Anencephaly	C10.500.680.196; C16.131.085.197; C16.131.666.680.196
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D052177	Kidney Diseases, Cystic	C12.050.351.968.419.403; C12.200.777.419.403; C12.950.419.403
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D016104	Oligohydramnios	C12.050.703.560
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D007690	Polycystic Kidney Diseases	C12.050.351.968.419.403.875; C12.200.777.419.403.875; C12.950.419.403.875; C16.131.077.717; C16.320.184.625
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600
D058499	Retinal Dystrophies	C11.768.585.658
C537430	Arima syndrome (supp.)
C567582	Joubert Syndrome 10 (supp.)
C567364	Joubert Syndrome 9 (supp.)
C567365	Meckel Syndrome, Type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
(+)-JQ1 compound	affects expression, increases reaction, decreases expression	4
sodium arsenite	decreases expression, decreases methylation, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Formaldehyde	increases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
decabromobiphenyl ether	affects expression	1
2,3-pentanedione	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Vorinostat	decreases expression	1
Panobinostat	affects expression, increases reaction	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Demecolcine	increases expression	1
Diacetyl	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0KQ	UNIBSi016-A	Induced pluripotent stem cell	Female
CVCL_A0KR	UNIBSi016-B	Induced pluripotent stem cell	Female
CVCL_A0KS	UNIBSi016-C	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

255 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT04705051	PHASE3	TERMINATED	Long-term Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) With Venglustat
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02684435	PHASE2	COMPLETED	Contrast-enhanced Ultrasound of the Kidney
NCT03196076	PHASE2	COMPLETED	Contrast-enhanced Ultrasound for Complex Kidney Lesion Diagnosis in Patients With CKD Extension
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT00031122	Not specified	UNKNOWN	Study of Genetic Risk Factors for Spina Bifida and Anencephaly
NCT00636233	Not specified	COMPLETED	Genetics of Spina Bifida and Anencephaly
NCT02371551	Not specified	COMPLETED	Evaluation of Complex Renal Cyst With CEUS/Functional MRI Versus CT
NCT04670887	Not specified	NOT_YET_RECRUITING	Comparison of Surgery and Active Surveillance in the Treatment of Bosniak III Renal Cysts
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy
NCT00001404	Not specified	COMPLETED	Phenotype and Etiology of Pallister-Hall Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy