CCN6
protein-codingcellular communication network factor 6, the group of Cellular communication network factors
Gene summary
This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene is overexpressed in colon tumors. It may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. Mutations of this gene are associated with progressive pseudorheumatoid dysplasia, an autosomal recessive skeletal disorder, indicating that the gene is essential for normal postnatal skeletal growth and cartilage homeostasis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
- WISP3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008827
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008827
Submitter: ClinGen
CCN6 was first reported in relation to autosomal recessive progressive pseudorheumatoid dysplasia (PPRD) in 1999 (Hurvitz et al. 1999 PMID: 10471507). PPRD is characterized by healthy at birth, onset of arthropathy early in childhood, usually between ages three and six years, enlargement of interphalangeal joints of hands, progressive restricted mobility of all joints, gait abnormalities, genu valgum / genu varum, progressive hip disease, articular pain, motor weakness and fatigability, spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk, adult height below the third centile, and absence of signs of inflammation. To date more than 200 families with molecularly confirmed PPRD have been reported. Only one disease assertion has been made thus far therefore we curate the following disease entity progressive pseudorheumatoid arthropathy of childhood (MONDO:0008827, OMIM:208230). 29 variants (11 frameshift, 9 missense, 5 nonsense, 4 splice site) that have been reported in 50 probands in 2 publications (PMID: 12819927, 22791401) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of CCN6 protein function which likely disrupts normal cartilage maintenance and bone growth, leading to the joint problems in PPRD. In summary, there is definitive evidence supporting the relationship between CCN6 and autosomal recessive PPRD. 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 Skeletal Disorders GCEP on the meeting date 09/04/2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0008827
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008827
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CCN6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_198239.2. 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 | 55 | 4 | 59 | |||
| missense | 5 | 8 | 65 | 10 | 3 | 91 |
| nonsense | 10 | 4 | 14 | |||
| start loss | 3 | 1 | 4 | |||
| frameshift | 29 | 4 | 1 | 34 | ||
| splice donor/acceptor (+/-2bp) | 4 | 2 | 6 | |||
| Total | 51 | 19 | 66 | 65 | 7 | 208 |
Highest pathogenic variant AF is 0.00014934845
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_937882.2 | 5 | MANE Select | |
| Ensembl | ENSP00000357655.4 | 5 | MANE Select | |
| RefSeq | NP_003871.1 | 5 | Standard | |
| Ensembl | ENSP00000230529.5 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ccn6 | Danio rerio | Structure: pharyngeal arch cartilage Quality: fragile abnormal |
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361714
- Coding exons
- 5
- Length
- 16897
- Individuals with no LoFs
- 125700
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 48
- Defined
- 125748
- p
- 0.000191
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.161 | 184 | 190 | 0.967 | 0.00000920 | 2435 |
| Missense (PolyPhen) | 65 | 76.724 | 0.8472 | 983 | ||
| Synonymous | 0.324 | 64 | 67.4 | 0.950 | 0.00000335 | 691 |
| Loss of Function | 2.04 | 8 | 17.1 | 0.467 | 8.21e-7 | 217 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Appears to be required for normal postnatal skeletal growth and cartilage homeostasis.;
Recessive Scores
- pRec
- 0.152
Intolerance Scores
- RVIS EVS
- 1.02
- RVIS percentile EVS
- 90.92
Essentials
- Essential (gene trap)
- N