CHD5

Chr 1

chromodomain helicase DNA binding protein 5

Also known as: CHD-5, PMNDS

NCBI Gene: 26038 ENSG00000116254 UniProt: O00258

The protein is a neuron-specific chromodomain helicase that functions in chromatin remodeling and gene transcription. Mutations cause Parenti-Mignot neurodevelopmental syndrome with autosomal dominant inheritance. CHD5 is highly constrained against loss-of-function variants (pLI ~1.0), indicating that even single functional copies are critical for normal neurodevelopment.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the chromodomain helicase DNA-binding protein family. Members of this family are characterized by a chromodomain, a helicase ATP-binding domain and an additional functional domain. This gene encodes a neuron-specific protein that may function in chromatin remodeling and gene transcription. This gene is a potential tumor suppressor gene that may play a role in the development of neuroblastoma. [provided by RefSeq, Feb 2012]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.16

Clinical Summary— CHD5

⚡

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

42 unique Pathogenic / Likely Pathogenic· 427 VUS of 565 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 8.44

OE 0.09 (0.05–0.16)

Highly constrained

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

Missense Constraint?

5.32Z-score

OE missense 0.56 (0.53–0.60)

668 obs / 1182.5 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.16)

0≤0.351.4

Missense OE?0.56 (0.53–0.60)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 9 / 100.2Missense obs/exp: 668 / 1182.5Syn Z: -0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCHD5-related neurodevelopmental disorder with intellectual disability, speech delay and epilepsyLOFAD

This gene — mechanism propensity

0.4090th %ile

GOF

0.3887th %ile

LOF

0.65top 25%

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

LOFprediction above median · 1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.16

Literature Evidence

LOFThompson et al. (2003) also noted that microdeletions in monosomy 1p36 syndrome would include the CHD5 gene, suggesting that haploinsufficiency of CHD5 may contribute to the neurologic and developmental problems seen in those patients.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 12592387 ↗

ClinVar Variant Classifications

565 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic34

VUS427

Likely Benign54

Benign19

Conflicting7

Pathogenic

Likely Pathogenic

427

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	0	0	0	8
Likely Pathogenic	13	20	1	0	34
VUS	4	397	24	2	427
Likely Benign	0	13	8	33	54
Benign	0	1	8	10	19
Conflicting	—				7
Total	25	431	41	45	549

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap CHD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →