EIF2AK1

protein-coding

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

Gene summary

The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

MANE transcript

NM_014413.4

Inheritance

ClinVar variants

U:170B:57

Top phenotype

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr7:6,022,247-6,059,175

External References & Databases

Ensembl (ENSG00000086232)

Transcript & Mutation Effects

hg38 • Region Span ~36.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030036

Submitter: G2P

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030036

Submitter: Ambry Genetics

leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030036

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeAD

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: 32197074

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2AK1 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 180

not specifiedTotal: 102

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeTotal: 12

EIF2AK1-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014413.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	37 clinvar	3 clinvar	45
missense			147 clinvar	12 clinvar	4 clinvar	163
nonsense			5 clinvar	1 clinvar		6
start loss			1 clinvar			1
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	170	50	7	227

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014413.4	RefSeq	NP_055228.2	15	MANE Select
ENST00000199389.11	Ensembl	ENSP00000199389.6	15	MANE Select
NM_001134335.2	RefSeq	NP_001127807.1	15	Standard
ENST00000422786.1	Ensembl	ENSP00000392734.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

protein kinase activity
eukaryotic translation initiation factor 2alpha kinase activity
ATP binding
heme binding
protein homodimerization activity

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000199389
Coding exons: 15
Length: 36981
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.434	312	334	0.933	0.0000181	4077
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.000033	0.000033	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.294

Intolerance Scores

LoFtool: 0.796
RVIS EVS: 0.36
RVIS percentile EVS: 74.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.371

Gene Damage Prediction

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