ERCC6

ERCC excision repair 6, chromatin remodeling factor, the group of ERCC excision repair associated|B-WICH chromatin-remodelling complex subunits

Basic information

Region (hg38): 10:49454168-49539538

Previous symbols: [ "CKN2" ]

Links

ENSG00000225830 ∙ NCBI:2074 ∙ OMIM:609413 ∙ HGNC:3438 ∙ Uniprot:P0DP91, Q03468 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cockayne syndrome type 2 (Definitive), mode of inheritance: AR
• Cockayne syndrome type 2 (Strong), mode of inheritance: AR
• UV-sensitive syndrome 1 (Strong), mode of inheritance: AR
• Cockayne syndrome type 2 (Strong), mode of inheritance: AR
• Cockayne syndrome type 2 (Definitive), mode of inheritance: AR
• COFS syndrome (Supportive), mode of inheritance: AR
• Cockayne syndrome type 2 (Supportive), mode of inheritance: AR
• UV-sensitive syndrome (Supportive), mode of inheritance: AR
• Cockayne syndrome type 2 (Strong), mode of inheritance: AR
• premature ovarian failure 11 (Limited), mode of inheritance: Unknown
• Cockayne spectrum with or without cerebrooculofacioskeletal syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Premature ovarian failure 11; Xeroderma Pigmentosum-Cockayne Syndrome; De Sanctis-Cacchione syndrome	AD/AR	Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Obstetric; Oncologic	In Cockayne syndrome, periodic surveillance for manifestations affecting the audiologic, ophthalmologic, hepatic, and other systems can be beneficial; Metronidazole should be avoided due to concerns of hepatic failure; Some individuals with Xeroderma Pigmentosum-Cockayne Syndromecan have predisposition to skin cancer; 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 for dermatologic manifestations can be beneficial; For Premature ovarian failure, genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency	Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Obstetric; Oncologic; Ophthalmologic	14246158; 5560051; 4211825; 4431498; 7264357; 3545087; 1372469; 9443879; 9777763; 10196384; 10767341; 10739753; 15486090; 18446857; 18628313;20456449; 20301571; 22466610; 26204423; 26218421
Individuals with Cockayne syndrome without skin sensitivity have been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERCC6 gene.

• not_provided (1565 variants)
• Cockayne_syndrome_type_2 (328 variants)
• Cerebrooculofacioskeletal_syndrome_1 (239 variants)
• Inborn_genetic_diseases (180 variants)
• Age_related_macular_degeneration_5 (157 variants)
• DE_SANCTIS-CACCHIONE_SYNDROME (152 variants)
• not_specified (122 variants)
• Premature_ovarian_failure_11 (80 variants)
• UV-sensitive_syndrome_1 (79 variants)
• Lung_cancer (73 variants)
• ERCC6-related_disorder (48 variants)
• Cockayne_syndrome (36 variants)
• COFS_syndrome (14 variants)
• Macular_degeneration (14 variants)
• Lung_carcinoma (6 variants)
• Intellectual_disability (5 variants)
• Cockayne_spectrum_with_or_without_cerebrooculofacioskeletal_syndrome (3 variants)
• PGBD3-related_disorder (3 variants)
• Cone-rod_dystrophy (2 variants)
• Genetic_non-acquired_premature_ovarian_failure (2 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 ERCC6 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000124.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		3	7	600	4	614
missense	5	16	435	94	6	556
nonsense	56	54	3			113
start loss						0
frameshift	91	64				155
splice donor/acceptor (+/-2bp)	5	45	1			51
Total	157	182	446	694	10

Highest pathogenic variant AF is 0.000249168

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERCC6	protein_coding	protein_coding	ENST00000355832	20	84171

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.16e-22	0.992	125530	0	218	125748	0.000867

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0981	772	780	0.990	0.0000441	9799
Missense in Polyphen		180	230.32	0.78152		2861
Synonymous	-0.851	318	299	1.06	0.0000175	2876
Loss of Function	2.96	46	73.3	0.627	0.00000459	852

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00156	0.00156
Ashkenazi Jewish	0.00	0.00
East Asian	0.000489	0.000489
Finnish	0.00153	0.00153
European (Non-Finnish)	0.00104	0.00104
Middle Eastern	0.000489	0.000489
South Asian	0.000621	0.000621
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Essential factor involved in transcription-coupled nucleotide excision repair which allows RNA polymerase II-blocking lesions to be rapidly removed from the transcribed strand of active genes. Upon DNA-binding, it locally modifies DNA conformation by wrapping the DNA around itself, thereby modifying the interface between stalled RNA polymerase II and DNA. It is required for transcription-coupled repair complex formation. It recruits the CSA complex (DCX(ERCC8) complex), nucleotide excision repair proteins and EP300 to the at sites of RNA polymerase II- blocking lesions. {ECO:0000269|PubMed:15548521, ECO:0000269|PubMed:16916636, ECO:0000269|PubMed:20541997, ECO:0000269|PubMed:22483866}.
• Disease: DISEASE: Cockayne syndrome B (CSB) [MIM:133540]: 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:10447254, ECO:0000269|PubMed:19894250, ECO:0000269|PubMed:9443879}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebro-oculo-facio-skeletal syndrome 1 (COFS1) [MIM:214150]: 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:19894250}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: De Sanctis-Cacchione syndrome (DSC) [MIM:278800]: An autosomal recessive syndrome consisting of xeroderma pigmentosum associated with severe neurological and developmental involvement. In addition to the clinical signs of xeroderma pigmentosum, patients present with mental retardation, dwarfism, gonadal hypoplasia, microcephaly and various neurologic complications of early onset. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 5 (ARMD5) [MIM:613761]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:16754848}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: UV-sensitive syndrome 1 (UVSS1) [MIM:600630]: An autosomal recessive disorder characterized by cutaneous photosensitivity and mild freckling in the absence of neurological abnormalities or skin tumors. {ECO:0000269|PubMed:15486090}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Nucleotide excision repair - Homo sapiens (human);B-WICH complex positively regulates rRNA expression;ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression;Positive epigenetic regulation of rRNA expression;DNA Repair;Epigenetic regulation of gene expression;Gene expression (Transcription);RNA Polymerase I Promoter Clearance;RNA Polymerase I Transcription;RNA Polymerase I Transcription Initiation;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: 0.469

Intolerance Scores

• loftool: 0.0666
• rvis_EVS: 1.49
• rvis_percentile_EVS: 95.32

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.652
• ghis: 0.499

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.826

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ercc6
• 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); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; hearing/vestibular/ear 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; 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); neoplasm; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; limbs/digits/tail phenotype

Zebrafish Information Network

• Gene name: ercc6
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: curved

Gene ontology

• Biological process: response to superoxide;transcription-coupled nucleotide-excision repair;base-excision repair;pyrimidine dimer repair;transcription elongation from RNA polymerase I promoter;transcription by RNA polymerase II;response to oxidative stress;activation of JNKK activity;activation of JUN kinase activity;intrinsic apoptotic signaling pathway in response to DNA damage;response to UV;response to toxic substance;response to X-ray;response to UV-B;response to gamma radiation;DNA duplex unwinding;regulation of DNA-templated transcription, elongation;positive regulation of DNA-templated transcription, elongation;multicellular organism growth;photoreceptor cell maintenance;positive regulation of DNA repair;positive regulation of gene expression, epigenetic;positive regulation of protein tyrosine kinase activity
• Cellular component: nucleus;nucleoplasm;nucleolus;transcription elongation factor complex
• Molecular function: DNA binding;DNA helicase activity;chromatin binding;protein binding;ATP binding;protein C-terminus binding;DNA-dependent ATPase activity;protein tyrosine kinase activator activity;protein-containing complex binding;protein N-terminus binding