CNOT2

Chr 12AD

CCR4-NOT transcription complex subunit 2

Also known as: CDC36, HSPC131, IDNADFS, NOT2, NOT2H

NCBI Gene: 4848 ENSG00000111596 OMIM: 604909

The protein is a component of the CCR4-NOT complex, which regulates mRNA deadenylation, degradation, and transcriptional repression, and is required for maintaining the complex's structural integrity. Mutations cause autosomal dominant intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of the multi-component CCR4-NOT complex. The CCR4-NOT complex regulates mRNA synthesis and degradation and is also thought to be involved in mRNA splicing, transport and localization. The encoded protein interacts with histone deacetylases and functions as a repressor of polymerase II transcription. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— CNOT2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 52 VUS of 91 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.03

OE 0.06 (0.02–0.19)

Highly constrained

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

Missense Constraint?

3.65Z-score

OE missense 0.40 (0.35–0.47)

119 obs / 295.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.19)

0≤0.351.4

Missense OE?0.40 (0.35–0.47)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 2 / 33.3Missense obs/exp: 119 / 295.4Syn Z: 0.94

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCNOT2-related neurodevelopmental disorder with hypotoniaLOFAD

This gene — mechanism propensity

0.2399th %ile

GOF

0.2099th %ile

LOF

0.86top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF · LOEUF 0.19

Literature Evidence

LOFCNOT2 haploinsufficiency causes a neurodevelopmental disorder with characteristic facial features.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31512373 ↗

ClinVar Variant Classifications

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic4

VUS52

Likely Benign10

Benign1

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	1	0	4
Likely Pathogenic	4	0	0	0	4
VUS	1	49	2	0	52
Likely Benign	0	5	3	2	10
Benign	0	0	1	0	1
Conflicting	—				2
Total	8	54	7	2	73

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap CNOT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →