NCBP2

Chr 3

nuclear cap binding protein subunit 2

Also known as: CBC2, CBP20, NIP1, PIG55

NCBI Gene: 22916 ENSG00000114503 UniProt: P52298 OMIM: 605133

NCBP2 encodes a component of the nuclear cap-binding complex that binds to the 5' cap of pre-mRNAs and regulates pre-mRNA splicing, mRNA export from the nucleus, and nonsense-mediated mRNA decay. Mutations cause autosomal recessive intellectual disability with seizures and dysmorphic features, typically presenting in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.675), suggesting some tolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene is a component of the nuclear cap-binding protein complex (CBC), which binds to the monomethylated 5' cap of nascent pre-mRNA in the nucleoplasm. The encoded protein has an RNP domain commonly found in RNA binding proteins, and contains the cap-binding activity. The CBC promotes pre-mRNA splicing, 3'-end processing, RNA nuclear export, and nonsense-mediated mRNA decay. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.68

Clinical Summary— NCBP2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

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ClinVar Variants

11 VUS of 19 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?

0.68LOEUF

pLI 0.400

Z-score 2.22

OE 0.21 (0.09–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.15Z-score

OE missense 0.40 (0.31–0.52)

40 obs / 100.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.21 (0.09–0.68)

0≤0.351.4

Missense OE?0.40 (0.31–0.52)

0≤0.61.4

Synonymous OE?1.33

0≤1.21.6

LoF obs/exp: 2 / 9.3Missense obs/exp: 40 / 100.7Syn Z: -1.58

This gene — mechanism propensity

0.6261th %ile

GOF

0.5660th %ile

LOF

0.53top 25%

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.

ClinVar Variant Classifications

19 submitted variants in ClinVar

ClinVar

Classification Summary

VUS11

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	11	0	11
Likely Benign	0	1	1
Benign	0	0	0
Total	11	1	12

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

View in ClinVar →

88 pathogenic / likely-pathogenic (of 110) ClinVar copy-number / structural variants overlap NCBP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →