C5

protein-coding

complement C5, the group of C3 and PZP like, alpha-2-macroglobulin domain containing|Complement system activation components|Receptor ligands

Gene summary

This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

MANE transcript

NM_001735.3

Inheritance

AR, AD

ClinVar variants

P:57U:350B:256

Top phenotype

Eculizumab, poor response to; Complement component 5 deficiency

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr9:120,932,987-121,075,195

External References & Databases

Ensembl (ENSG00000106804)

Transcript & Mutation Effects

hg38 • Region Span ~142.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complement component 5 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012295

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Eculizumab, poor response to; Complement component 5 deficiencyAD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Pharmacogenomic

Rationale: In Complement component 5 deficiency, antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Heterozygous variants have been described as resulting in poor response to eculizumab

Refs: 5411128; 4258194; 7730648; 21270745; 21635555; 22123893; 22668955; 23371790

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C5 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 768

not specifiedTotal: 192

Complement component 5 deficiencyTotal: 116

Eculizumab, poor response toTotal: 101

C5-related disorderTotal: 20

Prostate cancerTotal: 1

LathosterolosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001735.3. 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			7 clinvar	213 clinvar	4 clinvar	224
missense	2 clinvar		335 clinvar	37 clinvar	2 clinvar	376
nonsense	19 clinvar	2 clinvar	2 clinvar			23
start loss						0
frameshift	15 clinvar	2 clinvar				17
splice donor/acceptor (+/-2bp)	1 clinvar	16 clinvar	6 clinvar			23
Total	37	20	350	250	6	663

Highest pathogenic variant AF is 0.000079342055

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001735.3	RefSeq	NP_001726.2	41	MANE Select
ENST00000223642.3	Ensembl	ENSP00000223642.1	41	MANE Select
NM_001317163.2	RefSeq	NP_001304092.1	41	Standard
NM_001317164.2	RefSeq	NP_001304093.1	21	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)
Pertussis - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Staphylococcus aureus infection - Homo sapiens (human)

Biological Process

activation of MAPK activity
in utero embryonic development
chemotaxis
inflammatory response
complement activation, alternative pathway

Molecular Function

endopeptidase inhibitor activity
signaling receptor binding
protein binding
chemokine activity

Cellular Component

extracellular region
membrane attack complex
extracellular space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000223642
Coding exons: 41
Length: 97939
Individuals with no LoFs: 125577
Homozygous LoFs: 1
Heterozygous LoFs: 170
Defined: 125748
p: 0.000680

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.47	733	854	0.858	0.0000429	10961
Missense (PolyPhen)		145	229.43	0.632		2987
Synonymous	1.02	285	308	0.926	0.0000163	3114
Loss of Function	4.08	54	97.5	0.554	0.00000518	1216

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0023	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0010	0.0010	notable
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00082	0.00078	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled.;
Disease: DISEASE: Complement component 5 deficiency (C5D) [MIM:609536]: A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele. {ECO:0000269|PubMed:15995705}.;

Recessive Scores

pRec: 0.158

Intolerance Scores

LoFtool: 0.928
RVIS EVS: -0.05
RVIS percentile EVS: 49.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.771

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High