GeneBe

PRKRA

protein-coding

protein activator of interferon induced protein kinase EIF2AK2

Gene summary

This gene encodes a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. Mutations in this gene have been associated with dystonia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

MANE transcript

NM_003690.5

Inheritance

AR

ClinVar variants

P:4U:90B:26

Top phenotype

Dystonia 16

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr2:178,431,292-178,451,512

External References & Databases

Ensembl (ENSG00000180228)NCBI Gene (8575)OMIM (603424)HGNC:9438GenCCUniProt (O75569)AlphaFoldClinVar (PRKRA)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~20.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dystonia 16SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012789

Submitter: Orphanet

dystonia 16MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012789

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

dystonia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012789

Submitter: Genomics England PanelApp

dystonia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012789

Submitter: PanelApp Australia

dystonia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012789

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Dystonia 16AR

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 18243799; 18420150; 20408955; 22415584; 22842711; 25142429Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKRA variants in ClinVar

6 Conditions Cataloged
Dystonia 16Total: 103
not providedTotal: 41
Inborn genetic diseasesTotal: 18
not specifiedTotal: 14
PRKRA-related disorderTotal: 3
Tinnitus with mild cognitive impairment (MCI)Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003690.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
22
clinvar
1
clinvar
 25
missense
3
clinvar
59
clinvar
3
clinvar
 65
nonsense
2
clinvar
 2
start loss
1
clinvar
 1
frameshift
1
clinvar
1
clinvar
 2
splice donor/acceptor (+/-2bp)
25
clinvar
 25
Total1390251120

Highest pathogenic variant AF is 0.000081800405

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003690.5RefSeqNP_003681.18MANE Select
ENST00000325748.9EnsemblENSP00000318176.48MANE Select
NM_001139517.1RefSeqNP_001132989.17Standard
NM_001139518.1RefSeqNP_001132990.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ebola Virus Pathway on Host
  • Ebola Virus Pathway on Host
  • Gene expression (Transcription)
  • MicroRNA (miRNA) biogenesis
  • Small interfering RNA (siRNA) biogenesis

Biological Process

  • protein phosphorylation
  • immune response
  • negative regulation of cell population proliferation
  • response to virus
  • miRNA metabolic process

Molecular Function

  • RNA binding
  • double-stranded RNA binding
  • protein binding
  • enzyme activator activity
  • enzyme binding

Cellular Component

  • nucleoplasm
  • cytoplasm
  • cytosol
  • membrane
  • perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000325748
Coding exons
8
Length
20099
Individuals with no LoFs
125504
Homozygous LoFs
0
Heterozygous LoFs
244
Defined
125748
p
0.000971
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.581031590.6480.000007092044
Missense (PolyPhen)1453.2890.26272703
Synonymous0.9744655.20.8330.00000254570
Loss of Function2.71313.90.2165.87e-7192

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000630.00062rare
Latino/Admixed American0.000820.00081rare
Ashkenazi Jewish0.000400.00040rare
East Asian0.00150.0014notable
Finnish0.00210.0020notable
European (Non-Finnish)0.000920.00090rare
South Asian0.000830.00082rare
Other0.000830.00081rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.178

Intolerance Scores

LoFtool
0.296
RVIS EVS
0.33
RVIS percentile EVS
73.11

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
H
Indispensability pred.
N
Indispensability score
0.243

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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