GeneBe

EIF2AK2

protein-coding

eukaryotic translation initiation factor 2 alpha kinase 2, the group of Protein phosphatase 1 regulatory subunits|Eukaryotic translation initiation factor 2 alpha kinases

Gene summary

The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses. [provided by RefSeq, Jul 2021]

Previous symbols:
  • PRKR

MANE transcript

NM_001135651.3

Inheritance

AD, AR

ClinVar variants

P:11U:156B:65

Top phenotype

Dystonia 33

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr2:37,099,210-37,157,522

External References & Databases

Ensembl (ENSG00000055332)NCBI Gene (5610)OMIM (176871)HGNC:9437GenCCUniProt (P19525)AlphaFoldClinVar (EIF2AK2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~58.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukoencephalopathy, developmental delay, and episodic neurologic regression syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030035

Submitter: Ambry Genetics

leukoencephalopathy, developmental delay, and episodic neurologic regression syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030035

Submitter: Labcorp Genetics (formerly Invitae)

leukoencephalopathy, developmental delay, and episodic neurologic regression syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030035

Submitter: Illumina

dystonia 33LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030513

Submitter: Labcorp Genetics (formerly Invitae)

early-onset generalized limb-onset dystoniaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007492

Submitter: Orphanet

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

leukoencephalopathy, developmental delay, and episodic neurologic regression syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030035

Submitter: G2P

Clinical Genomic Database (CGD)

Dystonia 33AD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: Neurologic

Rationale: While individuals have not been responsive to levodopa, treatment with deep brain stimulation has been reported as beneficial

Refs: 32197074; 33236446; 33816657; 33866603Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2AK2 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 180
Inborn genetic diseasesTotal: 67
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndromeTotal: 18
Dystonia 33Total: 12
EIF2AK2-related disorderTotal: 7
not specifiedTotal: 5
Global developmental delayTotal: 3
Developmental regressionTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001135651.3. 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
6
clinvar
34
clinvar
4
clinvar
 44
missense
9
clinvar
132
clinvar
24
clinvar
2
clinvar
 167
nonsense
6
clinvar
 6
start loss
0
frameshift
4
clinvar
1
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
8
clinvar
 10
Total110156596232

Highest pathogenic variant AF is 0.000008275806

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001135651.3RefSeqNP_001129123.115MANE Select
ENST00000233057.9EnsemblENSP00000233057.415MANE Select
NM_001135652.2RefSeqNP_001129124.114Standard
NM_002759.4RefSeqNP_002750.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
  • Influenza A - Homo sapiens (human)
  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • Necroptosis - Homo sapiens (human)
  • Viral carcinogenesis - Homo sapiens (human)

Biological Process

  • activation of MAPKK activity
  • positive regulation of cytokine production
  • translation
  • protein phosphorylation
  • negative regulation of cell population proliferation

Molecular Function

  • RNA binding
  • double-stranded RNA binding
  • protein kinase activity
  • protein serine/threonine kinase activity
  • eukaryotic translation initiation factor 2alpha kinase activity

Cellular Component

  • nucleus
  • cytoplasm
  • cytosol
  • ribosome
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000233057
Coding exons
15
Length
57856
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125741
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.282222820.7860.00001423606
Missense (PolyPhen)43100.840.426441283
Synonymous-0.3731061011.050.00000545988
Loss of Function3.61930.50.2950.00000145411

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000550.000053rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser- 312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. {ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035}.;

Recessive Scores

pRec
0.294

Intolerance Scores

LoFtool
0.664
RVIS EVS
-0.67
RVIS percentile EVS
15.62

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.822

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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