C8B

Chr 1AR

complement C8 beta chain

ENSG00000021852 UniProt: P07358 OMIM: 120960

This gene encodes the beta subunit of complement component 8 (C8), which forms part of the membrane attack complex that creates pores in target cell membranes leading to cell lysis as part of the immune response. Mutations cause C8 deficiency type II, inherited in an autosomal recessive pattern, which results in increased susceptibility to recurrent meningococcal infections. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis (PubMed:22832194, PubMed:26841837, PubMed:27052168, PubMed:30552328, PubMed:7440581). The MAC is initiated by proteolytic cleavage of C5 into complement C5b in response to the classical, alternative, lectin and GZMK complement pathways (PubMed:30552328, PubMed:39914456, PubMed:39814882, PubMed:7440581). The complement pathways consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:30552328, PubMed:7440581). C8B, together with C8A and C8G, inserts into the target membrane, but does not form pores by itself (PubMed:30552328). During MAC assembly, associates with C5b, C6 and C7 to form the C5b8 intermediate complex that inserts into the target membrane and traverses the bilayer increasing membrane rigidity (PubMed:30552328, PubMed:6833260)

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.331 OMIM phenotype

Clinical Summary— C8B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.33LOEUF

pLI 0.000

Z-score 0.11

OE 0.98 (0.73–1.33)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.74Z-score

OE missense 1.12 (1.02–1.22)

351 obs / 313.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.98 (0.73–1.33)

0≤0.351.4

Missense OE?1.12 (1.02–1.22)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 29 / 29.6Missense obs/exp: 351 / 313.9Syn Z: -2.19

This gene — mechanism propensity

0.6357th %ile

GOF

0.5857th %ile

LOF

0.3356th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.