C9orf72
C9orf72-SMCR8 complex subunit, the group of DENN domain containing|SWC tripartite complex
Basic information
Region (hg38): 9:27535639-27573866
Links
Phenotypes
GenCC
Source:
- frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (Moderate), mode of inheritance: AD
- progressive myoclonus epilepsy (Limited), mode of inheritance: AD
- frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (Strong), mode of inheritance: AD
- frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | AD | General | 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 | Neurologic | 21944778; 21944779; 23551834; 23597494; 24027057 |
ClinVar
This is a list of variants' phenotypes submitted to
- Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (69 variants)
- Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (18 variants)
- not provided (7 variants)
- not specified (2 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the C9orf72 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 | 11 | |||||
| missense | 14 | 16 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 1 | 1 | 2 | |||
| non coding ? | 42 | 17 | 61 | |||
| Total | 0 | 0 | 60 | 5 | 23 |
Variants in C9orf72
This is a list of pathogenic ClinVar variants found in the C9orf72 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-27536399-C-T | Autism spectrum disorder | Uncertain significance (Jul 28, 2023) | ||
| 9-27546610-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27546688-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-27546767-A-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27546830-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27546892-G-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 12, 2018) | ||
| 9-27546974-T-G | Amyotrophic Lateral Sclerosis/Frontotemporal Dementia | Uncertain significance (Jun 14, 2016) | ||
| 9-27547022-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Likely benign (Jan 13, 2018) | ||
| 9-27547100-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Apr 27, 2017) | ||
| 9-27547172-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-27547178-C-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 12, 2018) | ||
| 9-27547212-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27547315-G-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27547322-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27547335-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-27547345-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27547399-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-27547438-CACAG-C | Amyotrophic Lateral Sclerosis/Frontotemporal Dementia | Uncertain significance (Jun 14, 2016) | ||
| 9-27547449-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-27547563-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27547585-C-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Benign (Jan 12, 2018) | ||
| 9-27547634-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27547659-C-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27547684-T-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-27547782-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | Uncertain significance (Jan 13, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| C9orf72 | protein_coding | protein_coding | ENST00000380003 | 10 | 27321 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.00000106 | 0.941 | 125717 | 0 | 28 | 125745 | 0.000111 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.244 | 240 | 251 | 0.957 | 0.0000122 | 3150 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000247 | 0.000240 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000165 | 0.000163 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000124 | 0.000123 |
| Middle Eastern | 0.000165 | 0.000163 |
| South Asian | 0.000144 | 0.000131 |
| Other | 0.000163 | 0.000163 |
dbNSFP
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}.;
- Pathway
- Mesodermal Commitment Pathway
(Consensus)
Intolerance Scores
- loftool
- 0.770
- rvis_EVS
- -0.56
- rvis_percentile_EVS
- 19.54
Haploinsufficiency Scores
- pHI
- 0.271
- hipred
- N
- hipred_score
- 0.333
- ghis
- 0.549
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- gene_indispensability_score
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- C9orf72
- 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); hematopoietic system 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); immune system phenotype; growth/size/body region phenotype; cellular phenotype;
Zebrafish Information Network
- Gene name
- zgc:100846
- Affected structure
- motor neuron
- Phenotype tag
- abnormal
- Phenotype quality
- branchiness
Gene ontology
- Biological process
- negative regulation of protein phosphorylation;endocytosis;autophagy;regulation of autophagy;positive regulation of macroautophagy;stress granule assembly;axon extension;regulation of actin filament organization;late endosome to lysosome transport;regulation of TORC1 signaling;negative regulation of GTP binding;regulation of autophagosome assembly
- Cellular component
- P-body;extracellular space;nucleus;cytoplasm;lysosome;endosome;autophagosome;cytoplasmic stress granule;dendrite;nuclear membrane;guanyl-nucleotide exchange factor complex;perikaryon;axonal growth cone;main axon;Atg1/ULK1 kinase complex
- Molecular function
- protein binding;Rab guanyl-nucleotide exchange factor activity;Rab GTPase binding