SDCCAG8
protein-codingSHH signaling and ciliogenesis regulator SDCCAG8, the group of MicroRNA protein coding host genes
Gene summary
This gene encodes a centrosome associated protein. This protein may be involved in organizing the centrosome during interphase and mitosis. Mutations in this gene are associated with retinal-renal ciliopathy. [provided by RefSeq, Oct 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~244.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014444
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014444
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0014444
Submitter: ClinGen
General Description: The SDCCAG8 gene (also known as NPHP10), which encodes a centromeric structural protein (PMID 12559564), was first reported in relation to retinal disease in 2010, in which 12 truncating variants were described in affected individuals with nephronophthisis-related ciliopathies (Otto et al., 2010. PMID 20835237); initial cloning and characterization of the gene occurred in murine tissues in 2003 (murine CCCAP, Kenedy et al., 2003. PMID 12559564). Missense variants in the SDCCAG8 gene were then found in multiple families diagnosed with either Senior-Loken syndrome or Bardet-Biedl syndrome (PMIDs 20835237 and 22190896). SDCCAG8-related ciliopathy is characterized by a broad spectrum of symptoms, including retinal degeneration and nephronophthisis or kidney failure, with or without hypogonadism, respiratory complications and cognitive impairment. To date, studies suggest that, unlike other ciliopathies, SDCCAG8-related ciliopathy notably does not include polydactyly (PMIDs 22626039, 22190896). SDCCAG8-related disease is inherited in an autosomal recessive pattern, with homozygous and compound heterozygous cases described in the literature. Because all cases with different diagnoses exhibit a dominant mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, SDCCAG8-related retinopathy. Summary of Case Level Data (9.2 points): 5 suspected disease-causing variants (4 truncating variants and 1 intronic variant) reported in 4 probands from different countries in 4 publications (PMIDs: 22190896, 20835237, 31534065, 22190896) were scored in this curation. Notably, to date, disease-causing missense variants have not been reported in the literature. All reported variants are deletions, nonsense or splicing variants (for splicing example, see PMID: 22190896). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Mechanism for Disease: The mechanism of pathogenicity appears to be loss of function, as multiple nonsense and splicing variants to be disease causing (PMID: 33910785, 24888636) and are characterized in the literature. A single intronic variant has also been reported to be disease causing (ClinVar ID: 60). However, some studies have suggested that missense variants might contribute to oligogenic inheritance of Mendelian ciliopathies (PMID 374231782, 35835773). Experimental Evidence: 5 POINTS The SDCCAG8 gene product has been extensively studied in murine and cell culture models (PMID 35131266, 35503560). Consistent with a critical role in ciliary formation health, SDCCAG8 is expressed in photoreceptors (PMID 24722439) and is essential for photoreceptor development (PMID 38049871). Multiple cell culture models support the role of SDCCAG8 in cellular ciliary structures, as SDCCAG8 localizes to ciliary structures in vitro (PMIDs 24722439, 27224062). Summary Statement: In summary, SDCCAG8 is definitively associated with retinal dystrophy; pathogenic variants are associated with autosomal recessive ciliopathy, manifesting in syndromic retinal dystrophy, kidney disease and other variable ciliary phenotypes. The association loss of function variants in SDCCAG8 has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0017842
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014444
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013326
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013326
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013326
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Endocrine
Rationale: Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
Comments: Renal transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SDCCAG8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006642.5. 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 | 10 | 150 | 160 | |||
| missense | 392 | 13 | 405 | |||
| nonsense | 15 | 13 | 1 | 29 | ||
| start loss | 2 | 2 | ||||
| frameshift | 18 | 23 | 3 | 44 | ||
| splice donor/acceptor (+/-2bp) | 4 | 20 | 10 | 34 | ||
| Total | 37 | 58 | 416 | 163 | 0 | 674 |
Highest pathogenic variant AF is 0.00009428957
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006633.1 | 18 | MANE Select | |
| Ensembl | ENSP00000355499.3 | 18 | MANE Select | |
| RefSeq | NP_001337175.1 | 11 | Standard | |
| RefSeq | NP_001337176.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sdccag8 | Danio rerio | Structure: pronephric tubule Quality: decreased width abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of PLK1 Activity at G2/M Transition
- Recruitment of mitotic centrosome proteins and complexes
- Loss of Nlp from mitotic centrosomes
- Loss of proteins required for interphase microtubule organization from the centrosome
- Centrosome maturation
Biological Process
- G2/M transition of mitotic cell cycle
- neuron migration
- centrosome cycle
- regulation of G2/M transition of mitotic cell cycle
- establishment of cell polarity
Molecular Function
- protein binding
Cellular Component
- centrosome
- centriole
- cytosol
- cell-cell junction
- centriolar satellite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366541
- Coding exons
- 18
- Length
- 244075
- Individuals with no LoFs
- 125647
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 101
- Defined
- 125748
- p
- 0.000402
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0986 | 367 | 362 | 1.01 | 0.0000177 | 4747 |
| Missense (PolyPhen) | 104 | 101.66 | 1.023 | 1497 | ||
| Synonymous | -0.522 | 145 | 137 | 1.06 | 0.00000730 | 1226 |
| Loss of Function | 2.71 | 25 | 44.5 | 0.562 | 0.00000208 | 541 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00061 | 0.00061 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.0011 | 0.0011 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00031 | 0.00031 | rare |
| South Asian | 0.00042 | 0.00042 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in the establishment of cell polarity and epithelial lumen formation (By similarity). May play a role in ciliogenesis. {ECO:0000250|UniProtKB:Q80UF4}.;
- Disease
- DISEASE: Bardet-Biedl syndrome 16 (BBS16) [MIM:615993]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:20835237, ECO:0000269|PubMed:22626039}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.115
Intolerance Scores
- LoFtool
- 0.879
- RVIS EVS
- -0.15
- RVIS percentile EVS
- 42.23
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.253
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |