CNTROB

Chr 17

centrobin, centriole duplication and spindle assembly protein

Also known as: LIP8, PP1221

NCBI Gene: 116840 ENSG00000170037 UniProt: Q8N137

The protein is required for centriole duplication and proper cytokinesis, with inhibition of centriole duplication leading to cytokinetic defects. Mutations cause autosomal dominant disease through a dominant-negative mechanism. The gene shows tolerance to loss-of-function variants based on constraint metrics, suggesting the pathogenic mechanism involves disruption of normal protein function rather than simple haploinsufficiency.

ResearchSummary from RefSeq, UniProt, Mechanism

This gene encodes a centrosomal protein that interacts with BRCA2, and is required for centriole duplication and cytokinesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— CNTROB

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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

142 VUS of 174 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.59

OE 0.62 (0.47–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.67Z-score

OE missense 0.92 (0.85–0.99)

501 obs / 545.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.47–0.83)

0≤0.351.4

Missense OE?0.92 (0.85–0.99)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 34 / 54.6Missense obs/exp: 501 / 545.3Syn Z: 0.56

This gene — mechanism propensity

0.6841th %ile

GOF

0.6442th %ile

LOF

0.3455th %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

174 submitted variants in ClinVar

ClinVar

Classification Summary

VUS142

Likely Benign11

142

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	141	0	142
Likely Benign	0	8	3	11
Benign	0	0	0	0
Total	1	149	3	153

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap CNTROB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →