ERCC2
ERCC excision repair 2, TFIIH core complex helicase subunit, the group of ERCC excision repair associated|General transcription factor IIH complex subunits|Xeroderma pigmentosum complementation groups|DNA helicases
Basic information
Region (hg38): 19:45349836-45370918
Previous symbols: [ "XPD" ]
Links
Phenotypes
GenCC
Source:
- cerebrooculofacioskeletal syndrome 2 (Definitive), mode of inheritance: AR
- sarcoma (Moderate), mode of inheritance: AR
- xeroderma pigmentosum group D (Strong), mode of inheritance: AR
- trichothiodystrophy 1, photosensitive (Strong), mode of inheritance: AR
- COFS syndrome (Supportive), mode of inheritance: AR
- xeroderma pigmentosum (Supportive), mode of inheritance: AR
- trichothiodystrophy (Supportive), mode of inheritance: AR
- xeroderma pigmentosum-Cockayne syndrome complex (Supportive), mode of inheritance: AR
- xeroderma pigmentosum group D (Definitive), mode of inheritance: AR
- trichothiodystrophy 1, photosensitive (Definitive), mode of inheritance: AR
- trichothiodystrophy 1, photosensitive (Definitive), mode of inheritance: AR
- trichothiodystrophy 1, photosensitive (Strong), mode of inheritance: AR
- xeroderma pigmentosum group D (Strong), mode of inheritance: AR
- xeroderma pigmentosum group D (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Trichothiodystrophy 1, photosensitive; Xeroderma pigmentosum, group D | AR | Allergy/Immunology/Infectious; Dermatologic; Oncologic | In Trichothiodystrophy, individuals may be at high risk for skin cancer, and preventive measures may be beneficial; Frequent infections have been reported, and prophylaxis and early and aggressive treatment of infections may be beneficial; In XP, skin lesions can be treated (and possibly prevented in some cases) with a variety of methods, depending on the specific type of lesion; Sun/UV exposure (and other agents, such as tobacco smoke) should be avoided; Periodic surveillance can be beneficial | Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic | 2189905; 1372108; 7802014; 8783572; 11709541; 11443545; 21959366; 20301571 |
ClinVar
This is a list of variants' phenotypes submitted to
- Inborn genetic diseases (954 variants)
- not provided (778 variants)
- Xeroderma pigmentosum, group D (117 variants)
- Cerebrooculofacioskeletal syndrome 2 (102 variants)
- Xeroderma pigmentosum (80 variants)
- not specified (66 variants)
- Trichothiodystrophy 1, photosensitive (38 variants)
- Trichothiodystrophy 1, photosensitive;Cerebrooculofacioskeletal syndrome 2;Xeroderma pigmentosum, group D (9 variants)
- Cerebrooculofacioskeletal syndrome 2;Xeroderma pigmentosum, group D;Trichothiodystrophy 1, photosensitive (8 variants)
- ERCC2-Related Disorders (6 variants)
- Ovarian cancer (4 variants)
- Xeroderma pigmentosum, group D;Trichothiodystrophy 1, photosensitive;Cerebrooculofacioskeletal syndrome 2 (4 variants)
- ERCC2-related condition (4 variants)
- Trichothiodystrophy (2 variants)
- Leukodystrophy (2 variants)
- Cerebrooculofacioskeletal syndrome 2;Trichothiodystrophy 1, photosensitive;Xeroderma pigmentosum, group D (2 variants)
- Malignant tumor of urinary bladder (1 variants)
- Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified (1 variants)
- Hypotrichosis simplex (1 variants)
- Craniopharyngioma (1 variants)
- Hepatoblastoma (1 variants)
- Bone osteosarcoma (1 variants)
- Cerebrooculofacioskeletal syndrome 1 (1 variants)
- ERCC2-related conditions (1 variants)
- Non-small cell lung carcinoma (1 variants)
- Corpus callosum, agenesis of (1 variants)
- Trichothiodystrophy 1, photosensitive;Xeroderma pigmentosum, group D (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERCC2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 446 | 456 | ||||
| missense | 13 | 645 | 675 | |||
| nonsense | 14 | 17 | 32 | |||
| start loss | 3 | |||||
| frameshift | 23 | 24 | 53 | |||
| inframe indel | 6 | |||||
| splice donor/acceptor (+/-2bp) | 29 | 33 | ||||
| splice region ? | 1 | 30 | 38 | 69 | ||
| non coding ? | 39 | 154 | 42 | 237 | ||
| Total | 48 | 87 | 701 | 611 | 48 |
Highest pathogenic variant AF is 0.000145
Variants in ERCC2
This is a list of pathogenic ClinVar variants found in the ERCC2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-45350344-T-G | not specified | Uncertain significance (Oct 25, 2022) | ||
| 19-45350361-G-C | not specified | Uncertain significance (Aug 04, 2023) | ||
| 19-45350363-A-G | not specified | Uncertain significance (May 11, 2022) | ||
| 19-45350543-G-A | not specified | Likely benign (Feb 15, 2023) | ||
| 19-45350548-A-C | not specified | Uncertain significance (Dec 15, 2022) | ||
| 19-45350647-C-T | not specified | Uncertain significance (Apr 13, 2022) | ||
| 19-45350648-G-A | not specified | Uncertain significance (Jan 23, 2024) | ||
| 19-45350666-C-T | not specified | Uncertain significance (Sep 27, 2021) | ||
| 19-45350675-G-A | not specified | Uncertain significance (Oct 06, 2022) | ||
| 19-45350720-G-A | not specified | Uncertain significance (Dec 21, 2022) | ||
| 19-45350720-G-C | not specified | Uncertain significance (Jan 09, 2024) | ||
| 19-45350732-C-T | not specified | Uncertain significance (May 01, 2022) | ||
| 19-45350738-G-A | not specified | Uncertain significance (Oct 12, 2023) | ||
| 19-45350968-T-C | not specified | Uncertain significance (Feb 22, 2023) | ||
| 19-45350988-G-A | not specified | Uncertain significance (Jan 16, 2024) | ||
| 19-45351301-C-A | not specified | Uncertain significance (Apr 11, 2023) | ||
| 19-45351317-G-A | not specified | Uncertain significance (Oct 03, 2022) | ||
| 19-45351327-C-T | Likely benign (May 01, 2022) | |||
| 19-45351328-G-A | not specified | Conflicting classifications of pathogenicity (Sep 13, 2023) | ||
| 19-45351352-C-T | not specified | Uncertain significance (Nov 27, 2023) | ||
| 19-45351405-G-A | Xeroderma pigmentosum, group D | Uncertain significance (Jan 13, 2018) | ||
| 19-45351413-C-T | Xeroderma pigmentosum, group D | Likely benign (Jan 13, 2018) | ||
| 19-45351423-G-GT | Xeroderma pigmentosum | Uncertain significance (Jun 14, 2016) | ||
| 19-45351448-C-A | Xeroderma pigmentosum, group D | Uncertain significance (Mar 30, 2018) | ||
| 19-45351457-C-T | Xeroderma pigmentosum, group D • Xeroderma pigmentosum, group D;Trichothiodystrophy 1, photosensitive;Cerebrooculofacioskeletal syndrome 2 | Likely benign (May 01, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| ERCC2 | protein_coding | protein_coding | ENST00000391945 | 23 | 21082 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 7.07e-20 | 0.0483 | 125582 | 0 | 166 | 125748 | 0.000660 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.380 | 454 | 477 | 0.951 | 0.0000341 | 4890 |
| Missense in Polyphen | 155 | 176.32 | 0.87909 | 1751 | ||
| Synonymous | -2.31 | 247 | 205 | 1.21 | 0.0000148 | 1531 |
| Loss of Function | 1.10 | 34 | 41.7 | 0.816 | 0.00000206 | 477 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000888 | 0.000869 |
| Ashkenazi Jewish | 0.000596 | 0.000595 |
| East Asian | 0.000326 | 0.000326 |
| Finnish | 0.000373 | 0.000370 |
| European (Non-Finnish) | 0.00101 | 0.00100 |
| Middle Eastern | 0.000326 | 0.000326 |
| South Asian | 0.000196 | 0.000196 |
| Other | 0.000653 | 0.000652 |
dbNSFP
Source:
- Function
- 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 required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre- initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. XPD/ERCC2 acts by forming a bridge between CAK and the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:15494306, ECO:0000269|PubMed:20797633, ECO:0000269|PubMed:8413672}.;
- Disease
- DISEASE: Xeroderma pigmentosum complementation group D (XP-D) [MIM:278730]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. Some XP-D patients present features of Cockayne syndrome, including cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:11709541, ECO:0000269|PubMed:15494306, ECO:0000269|PubMed:7585650, ECO:0000269|PubMed:7825573, ECO:0000269|PubMed:7849702, ECO:0000269|PubMed:9101292}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Trichothiodystrophy 1, photosensitive (TTD1) [MIM:601675]: A form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non- photosensitive forms of the disorder. TTD1 patients manifest cutaneous photosensitivity. {ECO:0000269|PubMed:11242112, ECO:0000269|PubMed:7920640, ECO:0000269|PubMed:8571952, ECO:0000269|PubMed:9195225, ECO:0000269|PubMed:9238033, ECO:0000269|PubMed:9758621}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebro-oculo-facio-skeletal syndrome 2 (COFS2) [MIM:610756]: A disorder of prenatal onset characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. COFS is considered to be part of the nucleotide-excision repair disorders spectrum that include also xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. {ECO:0000269|PubMed:11443545}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Fluoropyrimidine Pathway, Pharmacodynamics;Nucleotide excision repair - Homo sapiens (human);Doxorubicin Pathway (Cancer Cell), Pharmacodynamics;Basal transcription factors - Homo sapiens (human);Nucleotide Excision Repair ;Fluoropyrimidine Activity;Eukaryotic Transcription Initiation;DNA Repair;Disease;RNA Pol II CTD phosphorylation and interaction with CE during HIV infection;NoRC negatively regulates rRNA expression;Negative epigenetic regulation of rRNA expression;Formation of the HIV-1 Early Elongation Complex;Epigenetic regulation of gene expression;Gene expression (Transcription);Formation of HIV-1 elongation complex containing HIV-1 Tat;Tat-mediated elongation of the HIV-1 transcript;HIV Transcription Elongation;Formation of HIV elongation complex in the absence of HIV Tat;Generic Transcription Pathway;Transcription of the HIV genome;Late Phase of HIV Life Cycle;HIV Life Cycle;HIV Infection;RNA Polymerase II HIV Promoter Escape;RNA Polymerase II Pre-transcription Events;RNA Polymerase II Transcription Initiation;RNA Polymerase II Transcription Initiation And Promoter Clearance;RNA Pol II CTD phosphorylation and interaction with CE;Formation of RNA Pol II elongation complex ;RNA Polymerase I Promoter Clearance;HIV Transcription Initiation;RNA Polymerase II Transcription;Metabolism of RNA;Infectious disease;RNA Polymerase I Transcription Termination;RNA Polymerase I Transcription;RNA Polymerase II Transcription Elongation;RNA Polymerase I Transcription Initiation;RNA Polymerase I Promoter Escape;RNA Polymerase II Promoter Escape;RNA Polymerase I Chain Elongation;AndrogenReceptor;RNA Polymerase II Transcription Pre-Initiation And Promoter Opening;TP53 Regulates Transcription of DNA Repair Genes;Transcriptional Regulation by TP53;mRNA Capping;Formation of the Early Elongation Complex;Formation of Incision Complex in GG-NER;Dual Incision in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Formation of TC-NER Pre-Incision Complex;Dual incision in TC-NER;Gap-filling DNA repair synthesis and ligation in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair
(Consensus)
Recessive Scores
- pRec
- 0.771
Intolerance Scores
- loftool
- 0.408
- rvis_EVS
- -1.95
- rvis_percentile_EVS
- 1.89
Haploinsufficiency Scores
- pHI
- 0.408
- hipred
- Y
- hipred_score
- 0.761
- ghis
- 0.599
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.918
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |
Mouse Genome Informatics
- Gene name
- Ercc2
- Phenotype
- nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; neoplasm; pigmentation phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype;
Gene ontology
- Biological process
- regulation of mitotic recombination;nucleotide-excision repair, DNA duplex unwinding;response to hypoxia;in utero embryonic development;transcription-coupled nucleotide-excision repair;nucleotide-excision repair;nucleotide-excision repair, preincision complex stabilization;nucleotide-excision repair, preincision complex assembly;nucleotide-excision repair, DNA incision, 5'-to lesion;transcription initiation from RNA polymerase I promoter;termination of RNA polymerase I transcription;transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;transcription elongation from RNA polymerase II promoter;7-methylguanosine mRNA capping;protein phosphorylation;apoptotic process;response to oxidative stress;chromosome segregation;aging;cell population proliferation;response to UV;UV protection;post-embryonic development;viral process;spinal cord development;extracellular matrix organization;bone mineralization;central nervous system myelin formation;nucleotide-excision repair, DNA incision;multicellular organism growth;hair cell differentiation;embryonic cleavage;erythrocyte maturation;positive regulation of DNA binding;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of mitotic recombination;embryonic organ development;hair follicle maturation;hematopoietic stem cell differentiation;global genome nucleotide-excision repair;regulation of mitotic cell cycle phase transition
- Cellular component
- transcription factor TFIIH core complex;nucleus;nucleoplasm;transcription factor TFIID complex;transcription factor TFIIH holo complex;cytoplasm;spindle;cytosol;CAK-ERCC2 complex;MMXD complex
- Molecular function
- damaged DNA binding;ATP-dependent DNA helicase activity;protein kinase activity;protein binding;ATP binding;protein C-terminus binding;DNA-dependent ATPase activity;RNA polymerase II CTD heptapeptide repeat kinase activity;protein binding, bridging;5'-3' DNA helicase activity;ATP-dependent 5'-3' DNA helicase activity;metal ion binding;protein N-terminus binding;4 iron, 4 sulfur cluster binding