CYRIB

Chr 8

CYFIP related Rac1 interactor B

Also known as: BM-009, CYRI, CYRI-B, FAM49B, L1

NCBI Gene: 51571 ENSG00000153310 UniProt: Q9NUQ9 OMIM: 617978

The CYRIB protein negatively regulates RAC1 signaling and controls cytoskeletal remodeling, cell migration, and mitochondrial dynamics while also protecting against bacterial infections. Mutations cause autosomal dominant developmental and epileptic encephalopathy with microcephaly, affecting the brain and resulting in seizures and developmental delays typically beginning in infancy. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.31

Clinical Summary— CYRIB

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.31LOEUF

pLI 0.976

Z-score 3.76

OE 0.10 (0.04–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.21Z-score

OE missense 0.30 (0.24–0.38)

51 obs / 168.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.10 (0.04–0.31)

0≤0.351.4

Missense OE0.30 (0.24–0.38)

0≤0.61.4

Synonymous OE0.73

0≤1.21.6

LoF obs/exp: 2 / 20.3Missense obs/exp: 51 / 168.2Syn Z: 1.60

0.5477th %ile

GOF

0.71top 25%

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.