C9orf72

C9orf72-SMCR8 complex subunit, the group of DENN domain containing|SWC tripartite complex

Basic information

Region (hg38): 9:27535640-27573866

Links

ENSG00000147894 ∙ NCBI:203228 ∙ OMIM:614260 ∙ HGNC:28337 ∙ Uniprot:Q96LT7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the C9orf72 gene.

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			4	3	5	12
missense			14	2	1	17
nonsense			1			1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	2		3
non coding			42	2	17	61
Total	0	0	61	7	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: gnomAD

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: dbNSFP

• 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 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