ERCC8

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

Basic information

Region (hg38): 5:60866453-60945073

Previous symbols: [ "CKN1" ]

Links

ENSG00000049167 ∙ NCBI:1161 ∙ OMIM:609412 ∙ HGNC:3439 ∙ Uniprot:Q13216 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cockayne syndrome type 1 (Definitive), mode of inheritance: AR
• Cockayne syndrome type 1 (Definitive), mode of inheritance: AR
• Cockayne syndrome type 1 (Strong), mode of inheritance: AR
• UV-sensitive syndrome 2 (Strong), mode of inheritance: AR
• Cockayne syndrome type 1 (Strong), mode of inheritance: AR
• Cockayne syndrome type 2 (Supportive), mode of inheritance: AR
• UV-sensitive syndrome (Supportive), mode of inheritance: AR
• Cockayne syndrome type 1 (Definitive), mode of inheritance: AR
• Cockayne syndrome type 1 (Strong), mode of inheritance: AR
• Cockayne syndrome type 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cockayne syndrome A	AR	Neurologic	In Cockayne syndrome, some neurological manifestations have been reported as responding to treatment with carbidopa-levodopa	Dermatologic; Musculoskeletal; Neurologic	14783428; 1308368; 7664335; 9443879; 11185579; 14661080; 15744458; 16865293; 18695064;19329487; 19894250; 21108394; 26218421
UV-sensitive syndrome 2 has not been described as associated with increased risk of skin cancer

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERCC8 gene.

• not provided (367 variants)
• Cockayne syndrome type 1 (107 variants)
• Inborn genetic diseases (20 variants)
• Cockayne syndrome (10 variants)
• not specified (9 variants)
• Cockayne syndrome type 1;UV-sensitive syndrome 2 (4 variants)
• UV-sensitive syndrome 2;Cockayne syndrome type 1 (3 variants)
• ERCC8-related condition (2 variants)
• UV-sensitive syndrome 2 (1 variants)
• Abnormality of the nervous system (1 variants)
• See cases (1 variants)
• Hereditary breast ovarian cancer syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERCC8 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			1	100	4	105
missense	1	6	79	1		87
nonsense	19	15				34
start loss						0
frameshift	17	9	5			31
inframe indel		2	4			6
splice donor/acceptor (+/-2bp)	6	19	1			26
splice region		1	1	28	3	33
non coding		2	16	44	34	96
Total	43	53	106	145	38

Highest pathogenic variant AF is 0.0000329

Variants in ERCC8

This is a list of pathogenic ClinVar variants found in the ERCC8 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-60873852-T-G		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60873890-A-C		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60873891-G-C		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60873971-C-T		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60874013-G-C		Cockayne syndrome type 1	Uncertain significance (Apr 27, 2017)
5-60874032-A-G		Cockayne syndrome type 1	Benign (Jan 13, 2018)
5-60874096-G-T		Cockayne syndrome type 1	Benign (Jan 13, 2018)
5-60874153-A-T		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60874157-A-G		Cockayne syndrome type 1	Benign (Jan 13, 2018)
5-60874176-C-A		Cockayne syndrome type 1	Benign (Jan 13, 2018)
5-60874238-G-C		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60874239-C-CTGA		Cockayne syndrome	Uncertain significance (Jun 14, 2016)
5-60874378-A-G		Cockayne syndrome type 1	Benign/Likely benign (Jul 06, 2018)
5-60874499-A-G		Cockayne syndrome type 1	Uncertain significance (Jan 13, 2018)
5-60874502-T-C		Cockayne syndrome type 1	Uncertain significance (Jan 15, 2018)
5-60874510-A-G		Cockayne syndrome type 1	Benign (Jul 09, 2018)
5-60874579-G-A		Cockayne syndrome type 1	Benign (Jul 10, 2018)
5-60874608-A-T		Cockayne syndrome type 1	Uncertain significance (Jan 12, 2018)
5-60874613-ATTCATCC-A		Cockayne syndrome type 1	Uncertain significance (Mar 05, 2018)
5-60874616-C-T			Likely benign (Mar 29, 2020)
5-60874619-CCTT-C		Cockayne syndrome type 1	Uncertain significance (Feb 15, 2018)
5-60874623-C-T			Uncertain significance (Jul 19, 2022)
5-60874636-G-A			Likely benign (Jan 09, 2024)
5-60874642-G-A			Likely benign (Feb 14, 2021)
5-60874642-G-C			Likely benign (Sep 09, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERCC8	protein_coding	protein_coding	ENST00000265038	12	71243

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.80e-15	0.0184	125674	0	74	125748	0.000294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.402	221	205	1.08	0.00000931	2576
Missense in Polyphen		62	58.958	1.0516		756
Synonymous	-0.0870	72	71.1	1.01	0.00000336	725
Loss of Function	0.197	23	24.0	0.957	0.00000108	311

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000540	0.000540
Ashkenazi Jewish	0.00208	0.00209
East Asian	0.000218	0.000217
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000230	0.000229
Middle Eastern	0.000218	0.000217
South Asian	0.000229	0.000229
Other	0.00	0.00

dbNSFP

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.
• Pathway: Nucleotide excision repair - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);DNA Repair;Post-translational protein modification;Metabolism of proteins;Neddylation;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: 0.186

Intolerance Scores

• loftool: 0.619
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.7

Haploinsufficiency Scores

• pHI: 0.480
• hipred: Y
• hipred_score: 0.527
• ghis: 0.648

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.976

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ercc8
• Phenotype: neoplasm; hematopoietic system phenotype; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; vision/eye 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); hearing/vestibular/ear phenotype; growth/size/body region 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); homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: protein polyubiquitination;transcription-coupled nucleotide-excision repair;nucleotide-excision repair;cellular response to DNA damage stimulus;response to oxidative stress;response to UV;response to X-ray;response to auditory stimulus;response to organic cyclic compound;DNA duplex unwinding;proteasome-mediated ubiquitin-dependent protein catabolic process;post-translational protein modification;protein autoubiquitination
• Cellular component: nucleotide-excision repair complex;nucleus;nucleoplasm;cytoplasm;nuclear matrix;Cul4A-RING E3 ubiquitin ligase complex;protein-containing complex;perikaryon;Cul4-RING E3 ubiquitin ligase complex
• Molecular function: DNA helicase activity;ubiquitin-protein transferase activity;protein binding;DNA-dependent ATPase activity;protein-containing complex binding