C8A

protein-coding

complement C8 alpha chain, the group of Complement system activation components

Gene summary

C8 is a component of the complement system and contains three polypeptides, alpha, beta and gamma. This gene encodes the alpha subunit of C8. C8 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 complement C8 alpha-gamma deficiency. [provided by RefSeq, Nov 2008]

MANE transcript

NM_000562.3

Inheritance

ClinVar variants

P:28U:189B:142

Top phenotype

Complement component 8 deficiency, type I

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr1:56,854,768-56,918,223

External References & Databases

Ensembl (ENSG00000157131)

Transcript & Mutation Effects

hg38 • Region Span ~63.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

type I complement component 8 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013422

Submitter: Labcorp Genetics (formerly Invitae)

type I complement component 8 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013422

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Complement component 8 deficiency, type IAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

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

Refs: 6822660; 6433145; 9759902; 21270745; 22123893

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C8A variants in ClinVar

4 Conditions Cataloged

not providedTotal: 385

not specifiedTotal: 130

C8A-related disorderTotal: 15

Type I complement component 8 deficiencyTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000562.3. 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			2 clinvar	120 clinvar	1 clinvar	123
missense			184 clinvar	19 clinvar	2 clinvar	205
nonsense	13 clinvar	4 clinvar	2 clinvar			19
start loss						0
frameshift	5 clinvar		1 clinvar			6
splice donor/acceptor (+/-2bp)		6 clinvar				6
Total	18	10	189	139	3	359

Highest pathogenic variant AF is 0.000031469215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000562.3	RefSeq	NP_000553.1	11	MANE Select
ENST00000361249.4	Ensembl	ENSP00000354458.3	11	MANE Select
ENST00000695677.1	Ensembl	ENSP00000512097.1	11	Standard
ENST00000695677.2	Ensembl	ENSP00000512097.1	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

immune response
complement activation
complement activation, alternative pathway
complement activation, classical pathway
cytolysis

Molecular Function

complement binding
protein-containing complex binding

Cellular Component

extracellular region
membrane attack complex
extracellular space
membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361249
Coding exons: 11
Length: 63416
Individuals with no LoFs: 125676
Homozygous LoFs: 0
Heterozygous LoFs: 72
Defined: 125748
p: 0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.07	372	318	1.17	0.0000179	3841
Missense (PolyPhen)		106	103.81	1.0211		1270
Synonymous	-1.10	135	120	1.13	0.00000676	1073
Loss of Function	0.749	26	30.5	0.854	0.00000166	362

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00046	0.00046	rare
Other	0.00033	0.00033	rare

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. C8A inserts into the target membrane, but does not form pores by itself. {ECO:0000269|PubMed:17872444, ECO:0000269|PubMed:7440581}.;
Disease: DISEASE: Complement component 8 deficiency, 1 (C8D1) [MIM:613790]: A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.275
RVIS EVS: 1.58
RVIS percentile EVS: 95.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.764

Gene Damage Prediction

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