CBY1

Chr 22

chibby 1, beta catenin antagonist

Also known as: C22orf2, CBY, Chibby1, HS508I15A, PGEA1, PIGEA-14, PIGEA14, arb1

NCBI Gene: 25776 ENSG00000100211 UniProt: Q9Y3M2 OMIM: 607757

The protein encoded by CBY1 inhibits the Wnt signaling pathway by binding to beta-catenin and blocking its transcriptional activity, and also regulates intracellular protein trafficking including polycystin-2. Mutations cause autosomal recessive primary ciliary dyskinesia, a disorder affecting the respiratory system and other organs with motile cilia. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Beta-catenin is a transcriptional activator and oncoprotein involved in the development of several cancers. The protein encoded by this gene interacts directly with the C-terminal region of beta-catenin, inhibiting oncogenic beta-catenin-mediated transcriptional activation by competing with transcription factors for binding to beta-catenin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.50

Clinical Summary— CBY1

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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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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 5 VUS of 15 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.50LOEUF

pLI 0.001

Z-score 0.66

OE 0.73 (0.38–1.50)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.44Z-score

OE missense 0.86 (0.71–1.05)

69 obs / 80.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.38–1.50)

0≤0.351.4

Missense OE?0.86 (0.71–1.05)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 5 / 6.9Missense obs/exp: 69 / 80.0Syn Z: 0.35

This gene — mechanism propensity

0.84top 10%

GOF

0.6638th %ile

LOF

0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

15 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS5

Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	0	3	1	1	5
Likely Benign	0	0	0	0	0
Benign	0	0	0	0	0
Total	2	3	1	1	7

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap CBY1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →