• 30
    Haplo
    Score
  • 40
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
ERCC2 (HGNC:3434) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
ERCC excision repair 2, TFIIH core complex helicase subunit
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
XPD
Alias symbols
MAG, EM9, MGC102762, MGC126218, MGC126219
%HI
16.33(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
1.09(Read more about gnomAD LOEUF score)
Cytoband
19q13.32
Genomic Coordinates
GRCh37/hg19: chr19:45853095-45873831 NCBI Ensembl UCSC
GRCh38/hg38: chr19:45349837-45370573 NCBI Ensembl UCSC
MANE Select Transcript
NM_000400.4 ENST00000391945.10 (Read more about MANE Select)
Function
ATP-dependent 5'-3' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATP-dependent helicase activity of XPD/ERCC2 is requi... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-17631
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Gene Associated with Autosomal Recessive Phenotype (30)
Triplosensitivity:
Dosage Sensitivity Unlikely (40)
Last Evaluated:
06/13/2023

Haploinsufficiency (HI) Score Details

HI Score:
30
HI Evidence Strength:
Gene Associated with Autosomal Recessive Phenotype (Disclaimer)
HI Disease:
HI Evidence Comments:
Broughton et al. 2001, PMID:11709541 Two patients with features of both Xeroderma Pigmentosum (XP) and trichothiodystrophy, compound heterozygous pathogenic variants were detected in both patients. The 3-year-old girl carries a heterozygous frameshift variant (deletion of TT at 1781-1782) and a heterozygous in-frame in/del (deletion of AGA at 1823-1825 and insertion of TTTCGG). Another patient carries compound heterozygous missense pathogenic variants (p.Arg112His and p.Leu485Pro). Functional analysis of the skin fibroblasts demonstrated a hypersensitivity to UV irradiation and deficiency in repair synthesis measured by unscheduled DNA synthesis (UDS). This demonstrates the autosomal recessive nature of XP and trichothiodystrophy caused by ERCC2 variants. Fassihi et al 2016, PMID: 26884178 Deep phenotyping was carried out for 89 patients with Xeroderma Pigmentosum (XP) from UK national multidisciplinary XP service. 14 patients with XP-D Diagnosis are confirmed by clinical phenotype and the level of unscheduled DNA synthesis. Compound heterozygous pathogenic variants were detected in 12 patients and other two patients are homozygous. Loss-Of-Function (LOF) variants include: c.1867dupG, p.Val623fs; c.816-2A>G; c.1933_1934delCA, p.Gln645fs; c.718+1C>A; c.1827delC, p.Phe610fs; and c.1378-26_1383del32. This study further confirms the autosomal recessive nature of Xeroderma Pigmentosum caused by ERCC2 variants. ERCC2 heterozygous variants and cancer predisposition (Rump et al. 2016, PMID 27504877; Wang et al. 2022, PMID: 36066420; Yehia et al. 2018, PMID: 29684080; Chen et al. 2022, PMID: 35834270) Rump et al. analyzed ERCC2 variants in 1345 Caucasian index cases with Familial Breast- and/or Ovarian Cancer (BC/OC). Four LOF variants were detected (c.230_231delTG, p.Val77Alafs; c.1703_1704delTT, p.Phe568fs; c.2238delA, p.Ser746fs and c.1903-2A>G) , none of the recurrent ERCC2 variants showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. The LOF variants detected has population frequencies ranging from 0 to 0.0001 in gnomAD database. WES was carried out for 502 patients with familial nasopharyngeal carcinoma and 404 unaffected relatives and controls, the frequency of mutated genes was compared with 21 other familial caners in the UK biobank (N-5218). ERCC2 was found to be the most frequently mutated gene (1.39%). However, this frequency is not significantly different comparing to other familial cancers in the UK biobank. In a study of 87 Cowden/Cowden-like and Bannayan-Riley-Ruvalcaba syndromes patients without PTEN variant, a heterozygous ERCC2 variant (c.1703_1704delTT, p.Phe568fsTer2, rs587778271) was detected in one patient, however, the frequency of pathogenic variants identified in this series is not statistically enriched comparing to TCGA germline database. Among 3223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino and Native Hawaiian), patients with germline ERCC2 variant are significantly enriched in group with second primary cancer (HR, 3.51; 95% CI, 1.29-9.54). Conclusion: while heterozygous variants of the ERCC2 gene have been suggested to confer cancer predisposition, consistent results from different studies are still lacking. Currently, it is inconclusive that whether heterozygous variants of the ERCC2 gene confer cancer predisposition.

Triplosensitivity (TS) Score Details

TS Score:
40
TS Evidence Strength:
Dosage Sensitivity Unlikely (Disclaimer)
TS Evidence Comments:
Copy number gain of the ERCC2 gene has been reported in DGV Gold Standard (gssvG19162; gssvG19163). Therefore, the tripo-sensitivity of the ERCC2 gene is unlikely.

Genomic View

Select assembly: (NC_000019.9) (NC_000019.10)