CNOT2

Chr 12AD

CCR4-NOT transcription complex subunit 2

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

NCBI Gene: 4848ENSG00000111596UniProt: Q9NZN8

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomaliesMIM #618608
AD
90
ClinVar variants
25
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CNOT2
⚡
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.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 53 VUS of 90 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.40 (0.35–0.47)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88
0≤1.21.6
LoF obs/exp: 2 / 33.3Missense obs/exp: 119 / 295.4Syn Z: 0.94

ClinVar Variant Classifications

90 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic8
VUS53
Likely Benign9
Benign1
Conflicting2
17
Pathogenic
8
Likely Pathogenic
53
VUS
9
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
16
0
17
Likely Pathogenic
3
0
5
0
8
VUS
1
47
5
0
53
Likely Benign
0
5
3
1
9
Benign
0
0
1
0
1
Conflicting
—2
Total55230190

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

View in ClinVar →

Protein Context — Lollipop Plot

CNOT2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CNOT2-related neurodevelopmental disorder with hypotonia

strong
ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
stop lostmissense variantstop gained NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

MIM #618608

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.
Niceta M et al.·Clin Genet
2023Review
A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome.
Alesi V et al.·Am J Med Genet A
2019Review
The circular RNome of primary breast cancer.
Smid M et al.·Genome Res
2019
Clinical characterization of a patient with CNOT2 haploinsufficiency caused by a de novo partial deletion.
Rodrigues R et al.·Clin Dysmorphol
2023
Deciphering tissue-based proteome signatures revealed novel subtyping and prognostic markers for thymic epithelial tumors.
Ku X et al.·Mol Oncol
2020
Targeted RNA sequencing in the routine clinical detection of fusion genes in salivary gland tumors.
Bubola J et al.·Genes Chromosomes Cancer
2021
Reassessment of the 12q15 deletion syndrome critical region.
Alesi V et al.·Eur J Med Genet
2017Case report
Cross-platform assessment of genomic imbalance confirms the clinical relevance of genomic complexity and reveals loci with potential pathogenic roles in diffuse large B-cell lymphoma.
Dias LM et al.·Leuk Lymphoma
2016
Detailed genome-wide SNP analysis of major salivary carcinomas localizes subtype-specific chromosome sites and oncogenes of potential clinical significance.
Zhang L et al.·Am J Pathol
2013
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools