EIF2AK2

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

Basic information

Region (hg38): 2:37099209-37157522

Previous symbols: [ "PRKR" ]

Links

ENSG00000055332 ∙ NCBI:5610 ∙ OMIM:176871 ∙ HGNC:9437 ∙ Uniprot:P19525 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Moderate), mode of inheritance: AD
• early-onset generalized limb-onset dystonia (Supportive), mode of inheritance: AD
• leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Moderate), mode of inheritance: AD
• leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Strong), mode of inheritance: AD
• dystonia 33 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dystonia 33	AD/AR	Neurologic	While individuals have not been responsive to levodopa, treatment with deep brain stimulation has been reported as beneficial	Craniofacial; Musculoskeletal; Neurologic	32197074; 33236446; 33816657; 33866603

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EIF2AK2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EIF2AK2 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	19	5	27
missense		2	64	10	3	79
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)			2			2
splice region			3	5	3	11
non coding				16	5	21
Total	0	2	73	45	13

Variants in EIF2AK2

This is a list of pathogenic ClinVar variants found in the EIF2AK2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-37107284-G-A			Uncertain significance (Nov 01, 2022)
2-37107286-C-T			Uncertain significance (Mar 07, 2022)
2-37107298-T-C		Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome	Uncertain significance (Sep 26, 2022)
2-37107324-G-A			Likely benign (Nov 16, 2023)
2-37107332-G-C			Likely benign (Jul 26, 2022)
2-37107370-G-A		EIF2AK2-related disorder	Uncertain significance (Jan 23, 2024)
2-37107391-G-A			Uncertain significance (Jun 18, 2022)
2-37107409-G-A			Likely benign (Sep 16, 2022)
2-37107503-T-C		not specified	Uncertain significance (Jul 12, 2022)
2-37107509-C-T			Uncertain significance (Aug 01, 2023)
2-37107511-C-T			Uncertain significance (Dec 06, 2023)
2-37107512-G-A		Dystonia 33	Uncertain significance (Mar 29, 2024)
2-37107531-GA-G			Likely benign (Aug 16, 2022)
2-37107532-A-G			Likely benign (Dec 31, 2022)
2-37109178-T-C			Likely benign (Aug 08, 2023)
2-37109257-G-A			Benign (Nov 12, 2022)
2-37109260-G-C			Benign (Jan 29, 2024)
2-37109262-G-T			Uncertain significance (Aug 19, 2022)
2-37109287-C-T			Likely benign (May 01, 2023)
2-37109291-G-C		Global developmental delay;Leukoencephalopathy;Developmental regression • Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome	Conflicting classifications of pathogenicity (Jun 08, 2021)
2-37109305-C-T			Likely benign (Nov 03, 2023)
2-37114711-A-C			Benign (Jan 22, 2024)
2-37114756-G-A			Uncertain significance (Dec 15, 2023)
2-37114763-T-TA			Uncertain significance (Mar 12, 2023)
2-37114777-T-C			Benign (Nov 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EIF2AK2	protein_coding	protein_coding	ENST00000233057	15	57856

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0176	0.982	125727	0	14	125741	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.28	222	282	0.786	0.0000142	3606
Missense in Polyphen		43	100.84	0.42644		1283
Synonymous	-0.373	106	101	1.05	0.00000545	988
Loss of Function	3.61	9	30.5	0.295	0.00000145	411

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000188	0.000185
Ashkenazi Jewish	0.00	0.00
East Asian	0.000114	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000547	0.0000527
Middle Eastern	0.000114	0.000109
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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);Hepatitis C - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Translation Factors;PDGFR-beta pathway;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Type II interferon signaling (IFNG);double stranded rna induced gene expression;Disease;toll-like receptor pathway;Cytokine Signaling in Immune system;Inhibition of PKR;NS1 Mediated Effects on Host Pathways;Host Interactions with Influenza Factors;Influenza Infection;Infectious disease;Immune System;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;regulation of eif2;Signaling events mediated by TCPTP;ISG15 antiviral mechanism;Antiviral mechanism by IFN-stimulated genes;Interferon Signaling;PDGFR-beta signaling pathway;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.294

Intolerance Scores

• loftool: 0.664
• rvis_EVS: -0.67
• rvis_percentile_EVS: 15.62

Haploinsufficiency Scores

• pHI: 0.461
• hipred: Y
• hipred_score: 0.601
• ghis: 0.644

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.822

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eif2ak2
• Phenotype: cellular phenotype; immune 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); hematopoietic system phenotype

Gene ontology

• Biological process: activation of MAPKK activity;positive regulation of cytokine production;translation;protein phosphorylation;negative regulation of cell population proliferation;response to virus;response to toxic substance;regulation of translational initiation by eIF2 alpha phosphorylation;negative regulation of translation;peptidyl-tyrosine phosphorylation;evasion or tolerance by virus of host immune response;endoplasmic reticulum unfolded protein response;positive regulation of chemokine production;positive regulation of stress-activated MAPK cascade;negative regulation of osteoblast proliferation;cellular response to amino acid starvation;response to interferon-alpha;negative regulation of apoptotic process;regulation of phosphoprotein phosphatase activity;negative regulation of viral genome replication;innate immune response;protein autophosphorylation;positive regulation of NF-kappaB transcription factor activity;defense response to virus;regulation of NLRP3 inflammasome complex assembly;positive regulation of NIK/NF-kappaB signaling;regulation of hematopoietic progenitor cell differentiation;regulation of hematopoietic stem cell proliferation;regulation of hematopoietic stem cell differentiation
• Cellular component: nucleus;cytoplasm;cytosol;ribosome;membrane;cytosolic ribosome;perinuclear region of cytoplasm
• Molecular function: RNA binding;double-stranded RNA binding;protein kinase activity;protein serine/threonine kinase activity;eukaryotic translation initiation factor 2alpha kinase activity;non-membrane spanning protein tyrosine kinase activity;protein binding;ATP binding;protein phosphatase regulator activity;identical protein binding