ERCC6

Chr 10

ERCC excision repair 6, chromatin remodeling factor

Also known as: ARMD5, CKN2, COFS, COFS1, CSB, CSB-PGBD3, POF11, RAD26

NCBI Gene: 2074 ENSG00000225830 UniProt: Q03468

This gene encodes a DNA-binding protein essential for transcription-coupled nucleotide excision repair and chromatin remodeling, with DNA-dependent ATPase activity that removes DNA lesions and regulates double-strand break repair. Mutations cause autosomal recessive Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1, both early-onset multisystem disorders with neurodegeneration, growth failure, and photosensitivity. The protein is critical for neuronal differentiation and has very low tolerance for loss-of-function mutations (LOEUF 0.802).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.80

Clinical Summary— ERCC6

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Gene-Disease Validity (ClinGen)

Cockayne spectrum with or without cerebrooculofacioskeletal syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

362 unique Pathogenic / Likely Pathogenic· 619 VUS of 2087 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ERCC6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.80LOEUF

pLI 0.000

Z-score 2.96

OE 0.63 (0.49–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.10Z-score

OE missense 0.99 (0.93–1.05)

772 obs / 779.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.49–0.80)

0≤0.351.4

Missense OE?0.99 (0.93–1.05)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 46 / 73.3Missense obs/exp: 772 / 779.7Syn Z: -0.85

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveERCC6-related Cockayne syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6550th %ile

GOF

0.4085th %ile

LOF

0.3744th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

2087 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic174

Likely Pathogenic188

VUS619

Likely Benign888

Benign82

Conflicting120

174

Pathogenic

188

Likely Pathogenic

619

VUS

888

Likely Benign

Benign

120

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	158	6	10	0	174
Likely Pathogenic	172	9	7	0	188
VUS	7	547	58	7	619
Likely Benign	0	47	245	596	888
Benign	0	9	64	9	82
Conflicting	—				120
Total	337	618	384	612	2,071

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 96) ClinVar copy-number / structural variants overlap ERCC6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →