PRKN

parkin RBR E3 ubiquitin protein ligase, the group of RBR E3 ubiquitin ligases

Basic information

Region (hg38): 6:161347417-162727775

Previous symbols: [ "PARK2" ]

Links

ENSG00000185345 ∙ NCBI:5071 ∙ OMIM:602544 ∙ HGNC:8607 ∙ Uniprot:O60260 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive juvenile Parkinson disease 2 (Strong), mode of inheritance: AR
• autosomal recessive juvenile Parkinson disease 2 (Definitive), mode of inheritance: AR
• young-onset Parkinson disease (Supportive), mode of inheritance: AR
• Parkinson disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 2, autosomal recessive juvenile	AR	Neurologic	Individuals have been reported as responding to therapies such as levodopa	Neurologic	9560156; 10894217; 11487568; 11552035; 12056932; 12629236; 12891670; 12730996; 15266615; 15642918; 16130111; 16328510; 17187375; 20182943; 20837857; 20876472; 20558392

ClinVar

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

• not provided (22 variants)
• Autosomal recessive juvenile Parkinson disease 2 (10 variants)
• Young-onset Parkinson disease (2 variants)
• Autosomal recessive juvenile Parkinson disease 2;Neoplasm of ovary;Leprosy, susceptibility to, 2;Lung carcinoma (1 variants)
• Neoplasm of ovary;Lung cancer;Autosomal recessive juvenile Parkinson disease 2 (1 variants)
• PRKN-related disorder (1 variants)
• See cases (1 variants)
• Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKN 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			7	48	2	57
missense	6	7	107	11	4	135
nonsense	7	2				9
start loss		2				2
frameshift	6	4				10
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2	1				3
splice region	1		5	5		11
non coding	1		54	59	47	161
Total	22	16	169	118	53

Highest pathogenic variant AF is 0.00218

Variants in PRKN

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

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

Position	Type	Phenotype	Significance	ClinVar
6-161347571-CTG-C		Juvenile-onset Parkinson disease	Uncertain significance (Jun 14, 2016)
6-161347581-T-C		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Apr 27, 2017)
6-161347607-T-C		Autosomal recessive juvenile Parkinson disease 2	Benign (Jan 13, 2018)
6-161347611-T-C		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Feb 02, 2018)
6-161347613-G-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347619-G-T		Autosomal recessive juvenile Parkinson disease 2	Benign (Jan 13, 2018)
6-161347624-T-G		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347625-T-G		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347648-C-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347656-T-C		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347736-G-T		Juvenile-onset Parkinson disease	Uncertain significance (Jun 14, 2016)
6-161347745-G-A		Autosomal recessive juvenile Parkinson disease 2	Likely benign (Jan 12, 2018)
6-161347840-A-G		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347867-C-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347882-C-T		Autosomal recessive juvenile Parkinson disease 2	Likely benign (Jan 13, 2018)
6-161347885-G-A		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 12, 2018)
6-161347905-C-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 12, 2018)
6-161347907-C-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161347912-G-A		Autosomal recessive juvenile Parkinson disease 2	Likely benign (Jan 13, 2018)
6-161348077-A-G		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161348078-C-T		Autosomal recessive juvenile Parkinson disease 2	Benign (Jan 13, 2018)
6-161348102-C-T		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)
6-161348190-C-T		Autosomal recessive juvenile Parkinson disease 2	Likely benign (Jan 13, 2018)
6-161348404-C-T		Autosomal recessive juvenile Parkinson disease 2	Likely benign (Jan 13, 2018)
6-161348405-G-A		Autosomal recessive juvenile Parkinson disease 2	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKN	protein_coding	protein_coding	ENST00000366898	12	1380352

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.93e-7	0.976	125552	0	196	125748	0.000780

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.863	310	270	1.15	0.0000165	3049
Missense in Polyphen		131	120.84	1.0841		1359
Synonymous	-1.23	124	108	1.15	0.00000745	866
Loss of Function	2.10	14	25.4	0.551	0.00000119	303

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00163	0.00163
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000163	0.000163
Finnish	0.000462	0.000462
European (Non-Finnish)	0.00104	0.00104
Middle Eastern	0.000163	0.000163
South Asian	0.000196	0.000196
Other	0.000978	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:16135753, PubMed:21376232, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'- linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'- linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11590439, PubMed:11431533, PubMed:19229105, PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:25621951). Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in the regulation of neuron death (PubMed:21376232). Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene. {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:25621951}.
• Disease: DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236).; DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA- induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:9560156, ECO:0000269|PubMed:9731209}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in PRKN may be involved in the development and/or progression of ovarian cancer.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Parkin-Ubiquitin Proteasomal System pathway;Parkinsons Disease Pathway;role of parkin in ubiquitin-proteasomal pathway;Josephin domain DUBs;Post-translational protein modification;Metabolism of proteins;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Pink/Parkin Mediated Mitophagy;Amyloid fiber formation;Mitophagy;Class I MHC mediated antigen processing & presentation;alpha-synuclein and parkin-mediated proteolysis in parkinson`s disease;Deubiquitination;Alpha-synuclein signaling (Consensus)

Recessive Scores

• pRec: 0.478

Intolerance Scores

• rvis_EVS: 1.31
• rvis_percentile_EVS: 94.04

Haploinsufficiency Scores

• pHI: 0.184
• hipred: Y
• hipred_score: 0.727
• ghis: 0.428

Essentials

• essential_gene_gene_trap: N

Mouse Genome Informatics

• Gene name: Prkn
• Phenotype: respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal 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); 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); skeleton 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

Zebrafish Information Network

• Gene name: prkn
• Affected structure: fast muscle cell
• Phenotype tag: abnormal
• Phenotype quality: unlumenized

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;protein polyubiquitination;mitochondrial fission;autophagy of mitochondrion;mitophagy;negative regulation of protein phosphorylation;startle response;ubiquitin-dependent protein catabolic process;protein monoubiquitination;response to oxidative stress;mitochondrion organization;central nervous system development;learning;adult locomotory behavior;proteasomal protein catabolic process;regulation of autophagy;positive regulation of gene expression;negative regulation of gene expression;positive regulation of mitochondrial fusion;negative regulation of mitochondrial fusion;regulation of mitochondrion organization;regulation of glucose metabolic process;free ubiquitin chain polymerization;regulation of dopamine secretion;macroautophagy;protein ubiquitination;protein deubiquitination;regulation of protein ubiquitination;regulation of protein stability;protein destabilization;positive regulation of protein binding;negative regulation of actin filament bundle assembly;regulation of lipid transport;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;negative regulation of glucokinase activity;cellular response to unfolded protein;response to endoplasmic reticulum stress;synaptic transmission, glutamatergic;protein K29-linked ubiquitination;ERAD pathway;regulation of dopamine metabolic process;norepinephrine metabolic process;dopamine metabolic process;regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;proteasome-mediated ubiquitin-dependent protein catabolic process;positive regulation of DNA binding;negative regulation of neuron apoptotic process;cellular protein catabolic process;cellular protein metabolic process;protein K27-linked ubiquitination;negative regulation by host of viral genome replication;positive regulation of protein catabolic process;positive regulation of transcription by RNA polymerase II;negative regulation of JNK cascade;negative regulation of insulin secretion;protein stabilization;positive regulation of neurotransmitter uptake;dopamine uptake involved in synaptic transmission;protein autoubiquitination;regulation of mitochondrial membrane potential;zinc ion homeostasis;negative regulation of cell death;regulation of canonical Wnt signaling pathway;parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization;neuron cellular homeostasis;protein K63-linked ubiquitination;protein localization to mitochondrion;aggresome assembly;protein K48-linked ubiquitination;protein K11-linked ubiquitination;cellular response to manganese ion;protein K6-linked ubiquitination;negative regulation of canonical Wnt signaling pathway;positive regulation of mitochondrial fission;negative regulation of release of cytochrome c from mitochondria;cellular response to toxic substance;positive regulation of mitophagy in response to mitochondrial depolarization;mitochondrion to lysosome transport;regulation of cellular response to oxidative stress;negative regulation of neuron death;positive regulation of proteasomal protein catabolic process;negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator;negative regulation of primary amine oxidase activity;positive regulation of protein linear polyubiquitination;regulation of synaptic vesicle transport;negative regulation of oxidative stress-induced cell death;regulation of protein targeting to mitochondrion;positive regulation of tumor necrosis factor-mediated signaling pathway;cellular response to dopamine;negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway;negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway;negative regulation of exosomal secretion;positive regulation of autophagy of mitochondrion;positive regulation of dendrite extension;negative regulation of spontaneous neurotransmitter secretion;positive regulation of retrograde transport, endosome to Golgi;negative regulation of intralumenal vesicle formation;positive regulation of protein localization to membrane;regulation of reactive oxygen species metabolic process;negative regulation of reactive oxygen species metabolic process
• Cellular component: ubiquitin ligase complex;nucleus;cytoplasm;mitochondrion;endoplasmic reticulum;Golgi apparatus;cytosol;aggresome;nuclear speck;SCF ubiquitin ligase complex;neuron projection;perinuclear region of cytoplasm;LUBAC complex;Lewy body;presynapse;mitochondrion-derived vesicle;Parkin-FBXW7-Cul1 ubiquitin ligase complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;DNA-binding transcription repressor activity, RNA polymerase II-specific;G protein-coupled receptor binding;actin binding;ubiquitin-protein transferase activity;protein binding;beta-catenin binding;zinc ion binding;tubulin binding;SH3 domain binding;enzyme binding;kinase binding;protein kinase binding;PDZ domain binding;Hsp70 protein binding;heat shock protein binding;ubiquitin conjugating enzyme binding;ubiquitin protein ligase binding;identical protein binding;histone deacetylase binding;ubiquitin binding;phospholipase binding;chaperone binding;ubiquitin protein ligase activity;cullin family protein binding;ubiquitin-specific protease binding;F-box domain binding