EARS2

glutamyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class I

Basic information

Region (hg38): 16:23520754-23557731

Links

ENSG00000103356 ∙ NCBI:124454 ∙ OMIM:612799 ∙ HGNC:29419 ∙ Uniprot:Q5JPH6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (Strong), mode of inheritance: AR
• Leigh syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Combined oxidative phosphorylation deficiency 12	AR	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	Biochemical; Neurologic	22492562; 23008233

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EARS2 gene.

• not_provided (208 variants)
• Inborn_genetic_diseases (74 variants)
• Leukoencephalopathy-thalamus_and_brainstem_anomalies-high_lactate_syndrome (72 variants)
• not_specified (13 variants)
• EARS2-related_disorder (12 variants)
• Mitochondrial_disease (4 variants)
• See_cases (2 variants)
• Fetal_akinesia_deformation_sequence_1 (2 variants)
• Arthrogryposis_multiplex_congenita (2 variants)
• Motor_delay (1 variants)
• Limb_tremor (1 variants)
• Bilateral_tonic-clonic_seizure (1 variants)
• Combined_oxidative_phosphorylation_deficiency (1 variants)
• Global_developmental_delay (1 variants)
• Abnormal_pinna_morphology (1 variants)
• Prominent_forehead (1 variants)
• Abnormal_facial_shape (1 variants)
• High_palate (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EARS2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001083614.2. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	52	3	60
missense	3	16	141	14	1	175
nonsense	6	4	1			11
start loss	1					1
frameshift	4	3	1			8
splice donor/acceptor (+/-2bp)		2				2
Total	14	25	148	66	4

Highest pathogenic variant AF is 0.000308475

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EARS2	protein_coding	protein_coding	ENST00000449606	9	35718

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.12e-8	0.784	124756	0	60	124816	0.000240

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.108	303	308	0.983	0.0000184	3353
Missense in Polyphen		105	122.03	0.86048		1331
Synonymous	-0.451	132	126	1.05	0.00000698	1085
Loss of Function	1.48	16	23.8	0.672	0.00000117	256

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000427	0.000426
Ashkenazi Jewish	0.0000994	0.0000993
East Asian	0.000725	0.000723
Finnish	0.00	0.00
European (Non-Finnish)	0.000195	0.000194
Middle Eastern	0.000725	0.000723
South Asian	0.000362	0.000360
Other	0.000333	0.000330

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the attachment of glutamate to tRNA(Glu) in a two-step reaction: glutamate is first activated by ATP to form Glu-AMP and then transferred to the acceptor end of tRNA(Glu). {ECO:0000250}.
• Disease: DISEASE: Combined oxidative phosphorylation deficiency 12 (COXPD12) [MIM:614924]: An autosomal recessive, mitochondrial, neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability. {ECO:0000269|PubMed:22492562, ECO:0000269|PubMed:23008233, ECO:0000269|PubMed:26741492}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Porphyrin and chlorophyll metabolism - Homo sapiens (human);2-Hydroxyglutric Aciduria (D And L Form);Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Glutamate Metabolism;tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.386

Intolerance Scores

• loftool: 0.674
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.31

Haploinsufficiency Scores

• pHI: 0.0899
• hipred: N
• hipred_score: 0.204
• ghis: 0.507

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 0.979

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ears2

Gene ontology

• Biological process: glutamyl-tRNA aminoacylation;tRNA aminoacylation for mitochondrial protein translation
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: tRNA binding;glutamate-tRNA ligase activity;ATP binding;zinc ion binding;glutamate-tRNA(Gln) ligase activity