TNC
protein-codingtenascin C, the group of Tenascins
Gene summary
This gene encodes an extracellular matrix protein with a spatially and temporally restricted tissue distribution. This protein is homohexameric with disulfide-linked subunits, and contains multiple EGF-like and fibronectin type-III domains. It is implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity, and neuronal regeneration. [provided by RefSeq, Jul 2011]
- HXB
- DFNA56
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~98.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014283
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
TNC was first reported in relation to autosomal dominant sensorineural hearing loss in 2013 (Zhao et al., PMID: 23936043). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 3 variants (missense and nonsense) have been reported in humans (PMID: 23936043, 35062939). TNC has a gnomAD pLOF constraint score of 0.45 and lack of funcional assays call into question the pathogenicity of the reported nonsense variant. Therefore the two missense variants that have been reported in 2 probands in 1 publications (PMID: 23936043) are included in this curation. Missense variants in this gene segregated with the disease in 14 additional family members. This gene-disease association is supported by expression studies (PMIDs: 10102501, 22808246). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 3/20/18. It was reevaluated on 6/15/22. As a result of this reevaluation, new case-level information was incorporated and the overall classification remained at Limited.(SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014283
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
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
Comments: Deafness has been described as postlingual
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TNC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002160.4. 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 | 1 | 10 | 105 | 9 | 125 | |
| missense | 1 | 5 | 390 | 102 | 10 | 508 |
| nonsense | 7 | 7 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 14 | 15 | |||
| Total | 3 | 5 | 422 | 207 | 19 | 656 |
Highest pathogenic variant AF is 0.0002292231
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002151.2 | 27 | MANE Select | |
| Ensembl | ENSP00000265131.4 | 27 | MANE Select | |
| RefSeq | NP_001397920.1 | 25 | Standard | |
| RefSeq | NP_001425994.1 | 29 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tnc | Danio rerio | Structure: motor neuron Quality: increased branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- MicroRNAs in cancer - Homo sapiens (human)
- Human papillomavirus infection - Homo sapiens (human)
Biological Process
- osteoblast differentiation
- cell adhesion
- negative regulation of cell adhesion
- neuromuscular junction development
- positive regulation of cell population proliferation
Molecular Function
- extracellular matrix structural constituent
- protein binding
- syndecan binding
Cellular Component
- extracellular region
- basement membrane
- interstitial matrix
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000350763
- Coding exons
- 27
- Length
- 97731
- Individuals with no LoFs
- 125676
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 72
- Defined
- 125748
- p
- 0.000286
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0821 | 1296 | 1.29e+3 | 1.01 | 0.0000778 | 14375 |
| Missense (PolyPhen) | 488 | 535.97 | 0.9105 | 6125 | ||
| Synonymous | -0.333 | 528 | 518 | 1.02 | 0.0000337 | 4427 |
| Loss of Function | 5.95 | 30 | 91.4 | 0.328 | 0.00000471 | 1055 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00079 | 0.00078 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration. Promotes neurite outgrowth from cortical neurons grown on a monolayer of astrocytes. Ligand for integrins alpha-8/beta-1, alpha-9/beta-1, alpha-V/beta-3 and alpha-V/beta-6. In tumors, stimulates angiogenesis by elongation, migration and sprouting of endothelial cells (PubMed:19884327). {ECO:0000269|PubMed:19884327}.;
- Disease
- DISEASE: Deafness, autosomal dominant, 56 (DFNA56) [MIM:615629]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA56 is characterized by progressive hearing impairment with post-lingual onset. {ECO:0000269|PubMed:23936043}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.692
Intolerance Scores
- LoFtool
- 0.625
- RVIS EVS
- -0.2
- RVIS percentile EVS
- 38.99
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.662
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |