CC2D2A

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

Basic information

Region (hg38): 4:15469864-15601552

Links

ENSG00000048342 ∙ NCBI:57545 ∙ OMIM:612013 ∙ HGNC:29253 ∙ Uniprot:Q9P2K1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Joubert syndrome 9 (Definitive), mode of inheritance: AR
• Joubert syndrome 9 (Strong), mode of inheritance: AR
• Meckel syndrome (Supportive), mode of inheritance: AR
• Joubert syndrome with oculorenal defect (Supportive), mode of inheritance: AR
• COACH syndrome 1 (Supportive), mode of inheritance: AR
• retinitis pigmentosa 93 (Strong), mode of inheritance: AR
• Joubert syndrome 9 (Strong), mode of inheritance: AR
• ciliopathy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
COACH syndrome 2	AR	Gastrointestinal	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	Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary; Renal	18950740; 18387594; 18513680; 20301500; 20671153; 22246503; 22241855; 30267408
Digenic inheritance has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CC2D2A gene.

• Familial aplasia of the vermis;Meckel-Gruber syndrome (586 variants)
• Meckel-Gruber syndrome;Familial aplasia of the vermis (529 variants)
• not provided (473 variants)
• Joubert syndrome 9 (180 variants)
• Meckel syndrome, type 6 (155 variants)
• not specified (79 variants)
• Inborn genetic diseases (72 variants)
• CC2D2A-Related Disorders (38 variants)
• CC2D2A-related condition (20 variants)
• COACH syndrome 1 (12 variants)
• Meckel-Gruber syndrome (12 variants)
• Joubert syndrome 1 (7 variants)
• Familial aplasia of the vermis (7 variants)
• COACH syndrome 2 (4 variants)
• COACH syndrome 1;Meckel syndrome, type 6;Joubert syndrome 9 (4 variants)
• Retinitis pigmentosa 93;Joubert syndrome 9;COACH syndrome 2;Meckel syndrome, type 6 (4 variants)
• Neurodevelopmental disorder (4 variants)
• Meckel syndrome, type 6;Joubert syndrome 9;COACH syndrome 1 (4 variants)
• COACH syndrome 1;Joubert syndrome 9;Meckel syndrome, type 6 (4 variants)
• Meckel syndrome, type 6;Retinitis pigmentosa 93;Joubert syndrome 9;COACH syndrome 2 (3 variants)
• 7 conditions (2 variants)
• Meckel syndrome, type 6;Retinitis pigmentosa 93;COACH syndrome 2;Joubert syndrome 9 (2 variants)
• See cases (2 variants)
• Intellectual disability (2 variants)
• Joubert syndrome 9/15, digenic (2 variants)
• Joubert syndrome 9;COACH syndrome 2;Meckel syndrome, type 6;Retinitis pigmentosa 93 (2 variants)
• Retinitis pigmentosa 93;COACH syndrome 2;Meckel syndrome, type 6;Joubert syndrome 9 (2 variants)
• Renal cyst;Polydactyly;Anencephaly (2 variants)
• Polycystic kidney disease;Encephalocele (2 variants)
• Retinitis pigmentosa 93;Meckel syndrome, type 6;COACH syndrome 2;Joubert syndrome 9 (1 variants)
• Microcephaly (1 variants)
• Joubert syndrome and related disorders (1 variants)
• COACH syndrome 2;Meckel syndrome, type 6;Joubert syndrome 9 (1 variants)
• Joubert syndrome 9;COACH syndrome 2;Meckel syndrome, type 6 (1 variants)
• Pituitary stalk interruption syndrome (1 variants)
• COACH syndrome 2;Meckel syndrome, type 6;Joubert syndrome 9;Retinitis pigmentosa 93 (1 variants)
• Joubert syndrome 9;Meckel syndrome, type 6;COACH syndrome 2;Retinitis pigmentosa 93 (1 variants)
• Nephronophthisis (1 variants)
• - (1 variants)
• Meckel syndrome, type 6;Joubert syndrome 9;Retinitis pigmentosa 93;COACH syndrome 2 (1 variants)
• Abnormality of prenatal development or birth (1 variants)
• Neonatal encephalopathy (1 variants)
• Retinitis pigmentosa 93 (1 variants)
• Ciliopathy (1 variants)
• Meckel syndrome, type 6;COACH syndrome 2;Retinitis pigmentosa 93;Joubert syndrome 9 (1 variants)
• Polydactyly (1 variants)
• Meckel syndrome, type 6;COACH syndrome 1;Joubert syndrome 9 (1 variants)
• Joubert syndrome 9;Meckel syndrome, type 6;COACH syndrome 1 (1 variants)
• Joubert syndrome 9;Meckel syndrome, type 6;COACH syndrome 2 (1 variants)
• Joubert syndrome 9;COACH syndrome 1;Meckel syndrome, type 6 (1 variants)
• COACH syndrome 2;Joubert syndrome 9;Meckel syndrome, type 6;Retinitis pigmentosa 93 (1 variants)
• Meckel syndrome, type 6;Joubert syndrome 9;COACH syndrome 2;Retinitis pigmentosa 93 (1 variants)
• Retinal dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CC2D2A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			22	174	3	199
missense	11	17	543	20	2	593
nonsense	35	12	2		1	50
start loss						0
frameshift	34	15	3			52
inframe indel	2		12	1		15
splice donor/acceptor (+/-2bp)	7	23	2			32
splice region	1	1	43	42	2	89
non coding			13	172	73	258
Total	89	67	597	367	79

Highest pathogenic variant AF is 0.000282

Variants in CC2D2A

This is a list of pathogenic ClinVar variants found in the CC2D2A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-15469898-T-C		Meckel syndrome, type 6 • CC2D2A-related disorder • Joubert syndrome 9	Uncertain significance (Jan 13, 2018)
4-15469989-G-A		Joubert syndrome 9 • Meckel syndrome, type 6	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-15470029-G-A		Meckel syndrome, type 6 • Joubert syndrome 9	Uncertain significance (Jan 12, 2018)
4-15470094-G-C		not specified	Benign (May 11, 2021)
4-15473242-G-A		Joubert syndrome 9 • not specified • Meckel syndrome, type 6	Conflicting classifications of pathogenicity (Apr 01, 2023)
4-15473372-C-T			Benign (Jun 17, 2020)
4-15473476-A-G			Benign (Jan 28, 2020)
4-15473652-T-C			Uncertain significance (Jun 06, 2023)
4-15475937-A-G		Meckel-Gruber syndrome;Familial aplasia of the vermis	Uncertain significance (Jul 29, 2022)
4-15475939-C-A		Familial aplasia of the vermis;Meckel-Gruber syndrome	Uncertain significance (Apr 10, 2022)
4-15475942-A-G		Meckel syndrome, type 6 • Joubert syndrome 9 • Familial aplasia of the vermis;Meckel-Gruber syndrome	Uncertain significance (Oct 13, 2022)
4-15475944-G-A		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (May 31, 2023)
4-15475948-G-T		Meckel-Gruber syndrome;Familial aplasia of the vermis	Pathogenic (Feb 24, 2023)
4-15475955-TA-T		Meckel-Gruber syndrome;Familial aplasia of the vermis	Pathogenic (Apr 17, 2023)
4-15475957-A-T		Meckel-Gruber syndrome;Familial aplasia of the vermis	Pathogenic (Dec 01, 2023)
4-15475965-TAC-T		Familial aplasia of the vermis;Meckel-Gruber syndrome	Pathogenic (Dec 18, 2022)
4-15475977-T-A		Meckel-Gruber syndrome;Familial aplasia of the vermis	Uncertain significance (May 27, 2022)
4-15475978-G-A		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Jun 01, 2023)
4-15475979-G-A		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (Sep 19, 2022)
4-15475981-C-A		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (Sep 29, 2023)
4-15475983-C-CTTT		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (Oct 24, 2023)
4-15475987-G-C		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (Jun 27, 2023)
4-15475991-T-C		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Oct 09, 2023)
4-15476188-C-G			Benign (Jun 14, 2018)
4-15478449-T-C			Benign (Jun 19, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CC2D2A	protein_coding	protein_coding	ENST00000424120	36	131692

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.67e-27	0.997	124425	1	311	124737	0.00125

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.647	758	810	0.936	0.0000439	10538
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00264	0.00248
Ashkenazi Jewish	0.00233	0.00229
East Asian	0.000452	0.000445
Finnish	0.00331	0.00330
European (Non-Finnish)	0.00101	0.000964
Middle Eastern	0.000452	0.000445
South Asian	0.00130	0.00118
Other	0.00152	0.00149

dbNSFP

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.
• Pathway: Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.132

Intolerance Scores

• loftool: 0.546
• rvis_EVS: -0.92
• rvis_percentile_EVS: 9.83

Haploinsufficiency Scores

• pHI: 0.0992
• hipred: N
• hipred_score: 0.414
• ghis: 0.536

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0924

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cc2d2a
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye phenotype; renal/urinary system phenotype; embryo phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; cellular phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: cc2d2a
• Affected structure: retinal rod cell
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: neural tube closure;smoothened signaling pathway;determination of left/right symmetry;heart development;axoneme assembly;camera-type eye development;motile cilium assembly;cilium assembly;ciliary basal body-plasma membrane docking;protein localization to ciliary transition zone;non-motile cilium assembly;embryonic brain development
• Cellular component: cytosol;cytoskeleton;ciliary transition zone;MKS complex