C9

protein-coding

complement C9, the group of Complement system activation components

Gene summary

This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency. [provided by RefSeq, Feb 2009]

MANE transcript

NM_001737.5

Inheritance

ClinVar variants

P:52U:185B:123

Top phenotype

Complement component 9 deficiency

gnomAD constraint

pLI —, LoF o/e 1.14

Max pathogenic AF

—

Genomic locus

chr5:39,284,140-39,371,324

External References & Databases

Ensembl (ENSG00000113600)

Transcript & Mutation Effects

hg38 • Region Span ~87.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complement component 9 deficiencyMODERATE

Inheritance Pattern: Unknown

Disease ID:MONDO:0013445

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

complement component 9 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013445

Submitter: Ambry Genetics

complement component 9 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013445

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Complement component 9 deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Ophthalmologic

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis (including related to specific immunization) and early and aggressive treatment of infections may be beneficial

Comments: In some individuals, there has been no evidence of predicted sequelae (eg, Neisseria infections)

Refs: 7430628; 2744767; 8747118; 9703418; 10083734; 12596049; 15943177; 21270745; 22123893; 22381107; 24036952; 32246154

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C9 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 363

Inborn genetic diseasesTotal: 84

not specifiedTotal: 36

Complement component 9 deficiencyTotal: 23

C9-related disorderTotal: 21

Age related macular degeneration 15Total: 15

C9-related disordersTotal: 12

Primary ciliary dyskinesiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001737.5. 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			2 clinvar	94 clinvar	4 clinvar	100
missense	1 clinvar	1 clinvar	178 clinvar	25 clinvar		205
nonsense	15 clinvar	4 clinvar				19
start loss						0
frameshift	14 clinvar	9 clinvar	3 clinvar			26
splice donor/acceptor (+/-2bp)		8 clinvar	2 clinvar			10
Total	30	22	185	119	4	360

Highest pathogenic variant AF is 0.0011897788

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001737.5	RefSeq	NP_001728.1	11	MANE Select
ENST00000263408.5	Ensembl	ENSP00000263408.4	11	MANE Select
ENST00000509186.6	Ensembl	ENSP00000512235.1	11	Standard
ENST00000509186.7	Ensembl	ENSP00000512235.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prion diseases - Homo sapiens (human)
Complement and coagulation cascades - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)
Allograft Rejection

Biological Process

cell killing
complement activation, alternative pathway
complement activation, classical pathway
hemolysis by symbiont of host erythrocytes
regulation of complement activation

Cellular Component

extracellular region
membrane attack complex
extracellular space
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263408
Coding exons: 11
Length: 140607
Individuals with no LoFs: 125253
Homozygous LoFs: 0
Heterozygous LoFs: 494
Defined: 125747
p: 0.00197

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.587	326	297	1.10	0.0000155	3670
Missense (PolyPhen)		114	103.84	1.0979		1256
Synonymous	-0.805	115	105	1.10	0.00000560	1019
Loss of Function	-0.696	34	29.9	1.14	0.00000174	359

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0013	notable
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0.0026	0.0026	notable
East Asian	0.011	0.011	notable
Finnish	0.0049	0.0050	notable
European (Non-Finnish)	0.00064	0.00064	rare
South Asian	0.00072	0.00072	rare
Other	0.0023	0.0023	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells (PubMed:9634479, PubMed:9212048, PubMed:26841934). C9 is the pore- forming subunit of the MAC (PubMed:4055801, PubMed:26841934). {ECO:0000269|PubMed:26841934, ECO:0000269|PubMed:4055801, ECO:0000269|PubMed:9212048, ECO:0000269|PubMed:9634479}.;
Disease: DISEASE: Complement component 9 deficiency (C9D) [MIM:613825]: A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Some patients may develop dermatomyositis. {ECO:0000269|PubMed:9634479}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 15 (ARMD15) [MIM:615591]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:24036952}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.372
RVIS EVS: 1.45
RVIS percentile EVS: 95.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.462

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium