COPS6

protein-coding

COP9 signalosome subunit 6, the group of JAMM/MPN+ metallopeptidase family|COP9 signalosome

Gene summary

The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein belongs to translation initiation factor 3 (eIF3) superfamily. It is involved in the regulation of cell cycle and likely to be a cellular cofactor for HIV-1 accessory gene product Vpr. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006833.5

Inheritance

—

ClinVar variants

U:50B:1

Top phenotype

EBV-positive nodal T- and NK-cell lymphoma

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr7:100,088,969-100,092,187

External References & Databases

Ensembl (ENSG00000168090)

Transcript & Mutation Effects

hg38 • Region Span ~3.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COPS6 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 31

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006833.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar			4
missense			38 clinvar	1 clinvar		39
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	50	1	0	51

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006833.5	RefSeq	NP_006824.2	10	MANE Select
ENST00000303904.8	Ensembl	ENSP00000304102.3	10	MANE Select
ENST00000418625.5	Ensembl	ENSP00000400617.1	10	Standard
ENST00000418625.6	Ensembl	ENSP00000400617.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cops6	Danio rerio	Structure: pharyngeal arch cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

cops6

Danio rerio

Structure: pharyngeal arch cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide-binding Oligomerization Domain (NOD) pathway
DNA Repair
Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification

Biological Process

protein deneddylation
nucleotide-excision repair, DNA damage recognition
transcription-coupled nucleotide-excision repair
viral process
post-translational protein modification

Molecular Function

protein binding

Cellular Component

nucleoplasm
cytosol
COP9 signalosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303904
Coding exons: 10
Length: 3247
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.31	101	191	0.530	0.0000108	2160
Missense (PolyPhen)		28	74.335	0.37667		812
Synonymous	-1.04	86	74.6	1.15	0.00000474	620
Loss of Function	3.65	1	17.5	0.0573	8.85e-7	200

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Has some glucocorticoid receptor- responsive activity. Stabilizes COP1 through reducing COP1 auto- ubiquitination and decelerating COP1 turnover rate, hence regulates the ubiquitination of COP1 targets. {ECO:0000269|PubMed:11285227, ECO:0000269|PubMed:11337588, ECO:0000269|PubMed:12628923, ECO:0000269|PubMed:12732143, ECO:0000269|PubMed:21625211, ECO:0000269|PubMed:9535219}.;

Recessive Scores

pRec: 0.152

Intolerance Scores

LoFtool: 0.247
RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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