C9orf72
protein-codingC9orf72-SMCR8 complex subunit, the group of DENN domain containing|SWC tripartite complex
Gene summary
The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007105
Submitter: ClinGen
C9orf72 was first reported in relation to autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 1 in 2011 (PMID: 21944779, 21944778). Evidence supporting the gene-disease relationship includes case-level data, segregation data, case-control data and experimental data. Five variants (short tandem repeat expansions, missense and splice site) that have been reported in 8 probands in 7 publications (PMIDs: 21944778, 21944779, 22154785, 27790088, 26742954, 23597494, 27595458) are included in this curation. A GGGGCC hexanucleotide repeat expansion has been found to segregate with disease in at least 22 additional family members and is overrepresented in affected individuals in 9 independent case-control cohorts included here (PMID: 21944778, 21944779, 2215478, 22418734, 22300876, 23284068, 23254636, 23597494). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is currently unknown, however evidence supports 3 potential mechanisms, including RNA-based toxicity of the transcribed repeat; protein-based toxicity via translation of the expanded RNA to form dipeptide repeat proteins; and haploinsufficiency (PMID: 21944779, 24129584, 23393093, 25731823). This gene-disease association is also supported by expression studies, functional alteration assays and animal models. (PMIDs: 24166615, 24559645, 22366792, 27334615, 25977373, 27112499). More experimental evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, C9orf72 is definitively associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis. 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 ALS Gene Curation Expert Panel on the meeting date 26/08/2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0007105
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0020074
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007105
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 C9orf72 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018325.5. 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 | 5 | 6 | 4 | 15 | ||
| missense | 17 | 3 | 20 | |||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 28 | 9 | 4 | 41 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060795.1 | 10 | MANE Select | |
| Ensembl | ENSP00000369339.3 | 10 | MANE Select | |
| RefSeq | NP_001242983.1 | 10 | Standard | |
| RefSeq | NP_659442.2 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| zgc:100846 | Danio rerio | Structure: motor neuron Quality: branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mesodermal Commitment Pathway
Biological Process
- negative regulation of protein phosphorylation
- endocytosis
- autophagy
- regulation of autophagy
- positive regulation of macroautophagy
Molecular Function
- protein binding
- Rab guanyl-nucleotide exchange factor activity
- Rab GTPase binding
Cellular Component
- P-body
- extracellular space
- nucleus
- cytoplasm
- lysosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380003
- Coding exons
- 10
- Length
- 27321
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125745
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.244 | 240 | 251 | 0.957 | 0.0000122 | 3150 |
| Missense (PolyPhen) | 84 | 90.794 | 0.92517 | 1100 | ||
| Synonymous | -1.20 | 102 | 87.7 | 1.16 | 0.00000435 | 925 |
| Loss of Function | 1.82 | 13 | 22.3 | 0.584 | 0.00000110 | 288 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.00014 | 0.00013 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity (PubMed:27617292). Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation (PubMed:27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131). Plays a role in endosomal trafficking (PubMed:24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PubMed:27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation (PubMed:27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity). {ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27334615, ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292, ECO:0000269|PubMed:27723745, ECO:0000269|PubMed:28195531}.; FUNCTION: Isoform 2: Does not play a role in regulation of stress granule assembly in response to cellular stress. {ECO:0000269|PubMed:27037575}.;
Intolerance Scores
- LoFtool
- 0.770
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |