EIF2AK1

eukaryotic translation initiation factor 2 alpha kinase 1, the group of Eukaryotic translation initiation factor 2 alpha kinases

Basic information

Region (hg38): 7:6022246-6059175

Links

ENSG00000086232 ∙ NCBI:27102 ∙ OMIM:613635 ∙ HGNC:24921 ∙ Uniprot:Q9BQI3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (Limited), mode of inheritance: AD
• leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome	AD	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	32197074

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EIF2AK1 gene.

• not provided (1 variants)
• Leukodystrophy, hypomyelinating, 17 (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EIF2AK1 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			1	25	3	29
missense			75	2	5	82
nonsense			4			4
start loss			1			1
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			2	5		7
non coding	2	1	31	25	9	68
Total	2	1	115	52	17

Highest pathogenic variant AF is 0.0000460

Variants in EIF2AK1

This is a list of pathogenic ClinVar variants found in the EIF2AK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-6023300-C-G		Inborn genetic diseases	Uncertain significance (Dec 15, 2020)
7-6023301-A-G		Inborn genetic diseases • Leukodystrophy, hypomyelinating, 17	Pathogenic (May 04, 2022)
7-6023306-C-T		Inborn genetic diseases	Uncertain significance (Feb 10, 2022)
7-6023313-G-A		AIMP2-related disorder	Likely benign (Oct 29, 2021)
7-6023350-G-A		Inborn genetic diseases	Uncertain significance (May 16, 2021)
7-6023352-A-G			Likely benign (Aug 24, 2022)
7-6023355-C-T			Likely benign (Sep 17, 2022)
7-6023366-T-C			Uncertain significance (Dec 08, 2021)
7-6023368-G-C		Inborn genetic diseases	Uncertain significance (Mar 20, 2024)
7-6023371-C-T		Inborn genetic diseases	Uncertain significance (Nov 16, 2022)
7-6023372-G-A		Inborn genetic diseases	Uncertain significance (Dec 29, 2021)
7-6023380-TTC-T			Pathogenic (Aug 01, 2019)
7-6023380-TTCTC-T		Leukodystrophy, hypomyelinating, 17	Likely pathogenic (Aug 21, 2021)
7-6023382-C-G			Uncertain significance (Nov 02, 2023)
7-6023401-C-G			Uncertain significance (Aug 04, 2023)
7-6023405-A-G		Inborn genetic diseases	Uncertain significance (Sep 22, 2023)
7-6023408-C-T			Uncertain significance (Nov 26, 2021)
7-6023411-T-C			Uncertain significance (Mar 04, 2022)
7-6023415-C-T			Likely benign (Feb 22, 2022)
7-6023419-A-G			Uncertain significance (Jun 15, 2022)
7-6023425-A-G			Uncertain significance (Nov 22, 2022)
7-6023426-T-C		Inborn genetic diseases	Uncertain significance (Dec 21, 2023)
7-6023447-C-T		Inborn genetic diseases	Uncertain significance (Aug 06, 2022)
7-6023470-A-T		Inborn genetic diseases	Uncertain significance (Apr 18, 2023)
7-6023488-G-A			Uncertain significance (Dec 03, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EIF2AK1	protein_coding	protein_coding	ENST00000199389	15	36981

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.01e-7	0.999	125700	0	48	125748	0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.434	312	334	0.933	0.0000181	4077
Missense in Polyphen		67	97.993	0.68372		1207
Synonymous	-0.693	143	133	1.08	0.00000796	1205
Loss of Function	2.89	16	34.2	0.468	0.00000172	414

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000653	0.000653
Ashkenazi Jewish	0.00	0.00
East Asian	0.000277	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000186	0.000185
Middle Eastern	0.000277	0.000272
South Asian	0.0000328	0.0000327
Other	0.000497	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser- 48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions (By similarity). {ECO:0000250}.
• Pathway: Influenza A - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Translation Factors;regulation of eif2 (Consensus)

Recessive Scores

• pRec: 0.294

Intolerance Scores

• loftool: 0.796
• rvis_EVS: 0.36
• rvis_percentile_EVS: 74.63

Haploinsufficiency Scores

• pHI: 0.136
• hipred: Y
• hipred_score: 0.595
• ghis: 0.477

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.371

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eif2ak1
• Phenotype: homeostasis/metabolism phenotype; 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); hematopoietic system phenotype

Gene ontology

• Biological process: acute inflammatory response;phagocytosis;negative regulation of cell population proliferation;regulation of translational initiation by eIF2 alpha phosphorylation;regulation of eIF2 alpha phosphorylation by heme;macrophage differentiation;negative regulation of translational initiation by iron;protoporphyrinogen IX metabolic process;protein autophosphorylation;negative regulation of hemoglobin biosynthetic process;iron ion homeostasis;response to iron ion starvation
• Cellular component: cytoplasm
• Molecular function: protein kinase activity;eukaryotic translation initiation factor 2alpha kinase activity;ATP binding;heme binding;protein homodimerization activity