PRKRA

protein activator of interferon induced protein kinase EIF2AK2

Basic information

Region (hg38): 2:178431291-178451512

Links

ENSG00000180228 ∙ NCBI:8575 ∙ OMIM:603424 ∙ HGNC:9438 ∙ Uniprot:O75569 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• dystonia 16 (Strong), mode of inheritance: AR
• dystonia 16 (Moderate), mode of inheritance: AR
• dystonia 16 (Supportive), mode of inheritance: AR
• dystonia 16 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dystonia 16	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	18243799; 18420150; 20408955; 22415584; 22842711; 25142429

ClinVar

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

• Dystonia 16 (115 variants)
• not provided (50 variants)
• Dystonic disorder (15 variants)
• not specified (4 variants)
• Nonsyndromic Hearing Loss, Recessive (4 variants)
• Inborn genetic diseases (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKRA 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			3	11	2	16
missense	1	1	36	4	1	43
nonsense			1			1
start loss			2	1		3
frameshift			1	1		2
inframe indel			1		1	2
splice donor/acceptor (+/-2bp)			2			2
splice region			2	2	1	5
non coding			20	39	12	71
Total	1	1	66	56	16

Highest pathogenic variant AF is 0.0000920

Variants in PRKRA

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

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

Position	Type	Phenotype	Significance	ClinVar
2-178431442-A-G		Dystonia 16	Uncertain significance (Jan 13, 2018)
2-178431521-C-T		Dystonia 16	Uncertain significance (Jan 13, 2018)
2-178431521-C-CACA		Dystonic disorder	Benign (Jun 14, 2016)
2-178431544-T-C		Dystonia 16	Uncertain significance (Jan 12, 2018)
2-178431654-ACAAT-A		Dystonic disorder	Benign (Jun 14, 2016)
2-178431784-C-T		Dystonia 16	Conflicting classifications of pathogenicity (Jul 09, 2018)
2-178431832-T-G		Dystonia 16	Uncertain significance (Jan 13, 2018)
2-178431897-C-T		Dystonia 16	Benign/Likely benign (Jul 09, 2018)
2-178431899-G-A		Dystonia 16	Benign (Jul 09, 2018)
2-178431917-G-A		Dystonia 16	Uncertain significance (Jan 13, 2018)
2-178431938-A-G		Dystonia 16	Benign/Likely benign (Feb 04, 2019)
2-178431939-T-C		Dystonia 16	Conflicting classifications of pathogenicity (Jul 09, 2018)
2-178431946-T-A		Dystonia 16	Uncertain significance (Jan 12, 2018)
2-178432018-C-T		Dystonia 16	Uncertain significance (Jan 13, 2018)
2-178432066-C-T		Dystonia 16	Likely benign (Jan 13, 2018)
2-178432094-G-A		Dystonia 16	Benign (Aug 03, 2018)
2-178432116-A-G		Dystonia 16	Uncertain significance (Jul 23, 2020)
2-178432137-T-C		Dystonia 16	Uncertain significance (Dec 29, 2020)
2-178432148-A-G		Dystonia 16	Likely benign (Mar 02, 2020)
2-178432169-G-A		Dystonia 16	Uncertain significance (Jan 12, 2018)
2-178432178-G-A		Dystonia 16	Likely benign (Jul 14, 2022)
2-178432178-G-T		Dystonia 16	Uncertain significance (Sep 11, 2023)
2-178432185-T-C		Dystonia 16	Uncertain significance (May 25, 2022)
2-178432188-C-A		Dystonia 16	Uncertain significance (Sep 01, 2021)
2-178432199-G-A		Dystonia 16	Likely benign (Nov 28, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKRA	protein_coding	protein_coding	ENST00000325748	8	20099

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.417	0.582	125504	0	244	125748	0.000971

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.58	103	159	0.648	0.00000709	2044
Missense in Polyphen		14	53.289	0.26272		703
Synonymous	0.974	46	55.2	0.833	0.00000254	570
Loss of Function	2.71	3	13.9	0.216	5.87e-7	192

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00146	0.00144
Ashkenazi Jewish	0.000403	0.000397
East Asian	0.00146	0.00141
Finnish	0.00209	0.00203
European (Non-Finnish)	0.000915	0.000897
Middle Eastern	0.00146	0.00141
South Asian	0.000829	0.000817
Other	0.000833	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis. Required for siRNA production by DICER1 and for subsequent siRNA-mediated post- transcriptional gene silencing. Does not seem to be required for processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 association and sumoylation and phosphorylation of p53/TP53 at 'Lys-386' at 'Ser-392' respectively and enhances its activity in a EIF2AK2/PKR-dependent manner (By similarity). {ECO:0000250, ECO:0000269|PubMed:10336432, ECO:0000269|PubMed:11238927, ECO:0000269|PubMed:16424907, ECO:0000269|PubMed:16982605, ECO:0000269|PubMed:17452327, ECO:0000269|PubMed:9687506}.
• Disease: DISEASE: Dystonia 16 (DYT16) [MIM:612067]: An early-onset dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT16 patients have progressive, generalized dystonia with axial muscle involvement, oro-mandibular (sardonic smile) and laryngeal dystonia and, in some cases, parkinsonian features. {ECO:0000269|PubMed:18243799, ECO:0000269|PubMed:18420150}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Gene expression (Transcription);MicroRNA (miRNA) biogenesis;Small interfering RNA (siRNA) biogenesis;Ceramide signaling pathway;Gene Silencing by RNA (Consensus)

Recessive Scores

• pRec: 0.178

Intolerance Scores

• loftool: 0.296
• rvis_EVS: 0.33
• rvis_percentile_EVS: 73.11

Haploinsufficiency Scores

• pHI: 0.404
• hipred: Y
• hipred_score: 0.744
• ghis: 0.533

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: N
• gene_indispensability_score: 0.243

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prkra
• Phenotype: growth/size/body region phenotype; muscle phenotype; hearing/vestibular/ear phenotype; craniofacial phenotype; reproductive 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; limbs/digits/tail 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)

Gene ontology

• Biological process: protein phosphorylation;immune response;negative regulation of cell population proliferation;response to virus;miRNA metabolic process;viral process;production of siRNA involved in RNA interference;pre-miRNA processing;cellular response to oxidative stress;production of miRNAs involved in gene silencing by miRNA;outer ear morphogenesis;middle ear morphogenesis;positive regulation of catalytic activity;skeletal system morphogenesis;protein stabilization;positive regulation of intrinsic apoptotic signaling pathway
• Cellular component: nucleoplasm;cytoplasm;cytosol;membrane;perinuclear region of cytoplasm;RISC-loading complex
• Molecular function: RNA binding;double-stranded RNA binding;protein binding;enzyme activator activity;enzyme binding;identical protein binding;protein homodimerization activity;pre-miRNA binding