GeneBe

ERCC8

protein-coding

ERCC excision repair 8, CSA ubiquitin ligase complex subunit, the group of WD repeat domain containing|ERCC excision repair associated

Gene summary

This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

Previous symbols:
  • CKN1

MANE transcript

NM_000082.4

Inheritance

AR

ClinVar variants

P:154U:142B:146

Top phenotype

Cockayne syndrome A

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr5:60,866,454-60,945,073

External References & Databases

Ensembl (ENSG00000049167)NCBI Gene (1161)OMIM (609412)HGNC:3439GenCCUniProt (Q13216)AlphaFoldClinVar (ERCC8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~78.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

UV-sensitive syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013829

Submitter: Genomics England PanelApp

Cockayne syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: ClinGen

The ERCC8 gene is located on chromosome 5 at 5q12.1 and encodes the Excision Repair 8, CSA Ubiquitin Ligase Complex Subunit protein, a DNA-binding protein that is important in transcription-coupled excision repair. ERCC8 was first reported in relation to autosomal recessive Cockayne syndrome type 1/A in 1995 (Henning et al., PMID:7664335). Cockayne syndrome type 1 is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has fully manifested itself, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability, with death typically occurring in the first or second decade. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and severity. Therefore, the following disease entities have been split into multiple disease entities, Cockayne syndrome type 1 (OMIM: 216400) and UV-sensitive syndrome 2 (OMIM: 614621). 10 variants (nonsense, frameshift, canonical splice site, and missense) that have been reported in 5 probands in 2 publications (Cao et al., 2004, PMID:14661080; Calmels et al., 2018, PMID:29572252) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease relationship is also supported by experimental evidence (biochemical function and rescue) (Bregman et al., 1996, PMID:8876179; Houser et al., 1996, PMID:12509261; Ren et al., 2003, PMID:12655141). One mouse model demonstrated that homozygous LOF in ERCC8 results in defective transcription coupled-nucleotide excision repair in response to UV-light damage, a biochemical function and functional alteration also seen in ERCC6. In immortalized Cockayne syndrome type 1 cells with variants in ERCC8 knock-in of the wild-type protein restored the cells’ response to UV-light damange. Patient and cultured cells alike, similarly are less able to survive and/or synthesize DNA following UV irradiation in comparison to WT controls. In summary, ERCC8 is definitively associated with autosomal recessive Cockayne syndrome type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date July 15, 2022 (SOP Version 9).

Cockayne syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: Labcorp Genetics (formerly Invitae)

Cockayne syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: PanelApp Australia

Cockayne syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: Genomics England PanelApp

UV-sensitive syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015797

Submitter: Orphanet

Cockayne syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019570

Submitter: Orphanet

Cockayne syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: Myriad Women's Health

Cockayne syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: G2P

Cockayne syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019569

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Cockayne syndrome AAR

Manifestation: Dermatologic; Musculoskeletal; Neurologic

Intervention: Neurologic

Rationale: In Cockayne syndrome, some neurological manifestations have been reported as responding to treatment with carbidopa-levodopa

Comments: UV-sensitive syndrome 2 has not been described as associated with increased risk of skin cancer

Refs: 14783428; 1308368; 7664335; 9443879; 11185579; 14661080; 15744458; 16865293; 18695064;19329487; 19894250; 21108394; 26218421Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERCC8 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 436
Cockayne syndrome type 1Total: 153
Inborn genetic diseasesTotal: 64
UV-sensitive syndrome 2Total: 41
not specifiedTotal: 18
Cockayne syndromeTotal: 15
ERCC8-related disorderTotal: 7
ERCC8-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000082.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
139
clinvar
3
clinvar
 144
missense
2
clinvar
13
clinvar
131
clinvar
4
clinvar
 150
nonsense
25
clinvar
18
clinvar
 43
start loss
1
clinvar
1
clinvar
 2
frameshift
42
clinvar
19
clinvar
6
clinvar
 67
splice donor/acceptor (+/-2bp)
6
clinvar
26
clinvar
4
clinvar
 36
Total77771421433442

Highest pathogenic variant AF is 0.00004647514

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000082.4RefSeqNP_000073.112MANE Select
ENST00000676185.1EnsemblENSP00000501614.112MANE Select
NM_001007233.3RefSeqNP_001007234.110Standard
NM_001007234.3RefSeqNP_001007235.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Nucleotide excision repair - Homo sapiens (human)
  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • DNA Repair
  • Post-translational protein modification
  • Metabolism of proteins

Biological Process

  • protein polyubiquitination
  • transcription-coupled nucleotide-excision repair
  • nucleotide-excision repair
  • cellular response to DNA damage stimulus
  • response to oxidative stress

Molecular Function

  • DNA helicase activity
  • ubiquitin-protein transferase activity
  • protein binding
  • DNA-dependent ATPase activity
  • protein-containing complex binding

Cellular Component

  • nucleotide-excision repair complex
  • nucleus
  • nucleoplasm
  • cytoplasm
  • nuclear matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000265038
Coding exons
12
Length
71243
Individuals with no LoFs
125674
Homozygous LoFs
0
Heterozygous LoFs
74
Defined
125748
p
0.000294
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.4022212051.080.000009312576
Missense (PolyPhen)6258.9581.0516756
Synonymous-0.08707271.11.010.00000336725
Loss of Function0.1972324.00.9570.00000108311

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish0.00210.0021notable
East Asian0.000220.00022rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000230.00023rare
South Asian0.000230.00023rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair. The CSA complex (DCX(ERCC8) complex) promotes the ubiquitination and subsequent proteasomal degradation of ERCC6 in a UV-dependent manner; ERCC6 degradation is essential for the recovery of RNA synthesis after transcription-coupled repair. It is required for the recruitment of XAB2, HMGN1 and TCEA1/TFIIS to a transcription- coupled repair complex which removes RNA polymerase II-blocking lesions from the transcribed strand of active genes. {ECO:0000269|PubMed:16751180, ECO:0000269|PubMed:16916636, ECO:0000269|PubMed:16964240}.;
Disease
DISEASE: Cockayne syndrome A (CSA) [MIM:216400]: A rare disorder characterized by cutaneous sensitivity to sunlight, abnormal and slow growth, cachectic dwarfism, progeroid appearance, progressive pigmentary retinopathy and sensorineural deafness. There is delayed neural development and severe progressive neurologic degeneration resulting in mental retardation. Two clinical forms are recognized: in the classical form or Cockayne syndrome type 1, the symptoms are progressive and typically become apparent within the first few years or life; the less common Cockayne syndrome type 2 is characterized by more severe symptoms that manifest prenatally. Cockayne syndrome shows some overlap with certain forms of xeroderma pigmentosum. Unlike xeroderma pigmentosum, patients with Cockayne syndrome do not manifest increased freckling and other pigmentation abnormalities in the skin and have no significant increase in skin cancer. {ECO:0000269|PubMed:14661080, ECO:0000269|PubMed:15744458, ECO:0000269|PubMed:19894250}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: UV-sensitive syndrome 2 (UVSS2) [MIM:614621]: An autosomal recessive disorder characterized by cutaneous photosensitivity and mild freckling in the absence of neurological abnormalities or skin tumors. {ECO:0000269|PubMed:19329487}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.186

Intolerance Scores

LoFtool
0.619
RVIS EVS
-0.53
RVIS percentile EVS
20.7

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.976

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.