NARS2

asparaginyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class II

Basic information

Region (hg38): 11:78435620-78575194

Previous symbols: [ "DFNB94" ]

Links

ENSG00000137513 ∙ NCBI:79731 ∙ OMIM:612803 ∙ HGNC:26274 ∙ Uniprot:Q96I59 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hearing loss, autosomal recessive 94 (Limited), mode of inheritance: AR
• combined oxidative phosphorylation defect type 24 (Strong), mode of inheritance: AR
• combined oxidative phosphorylation defect type 24 (Moderate), mode of inheritance: AD
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• combined oxidative phosphorylation defect type 24 (Supportive), mode of inheritance: AR
• mitochondrial disease (Moderate), mode of inheritance: AR
• hearing loss, autosomal recessive 94 (Limited), mode of inheritance: AR
• combined oxidative phosphorylation defect type 24 (Strong), mode of inheritance: AR
• Leigh syndrome (Limited), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Limited), mode of inheritance: AR
• combined oxidative phosphorylation defect type 24 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 94	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic	25385316; 25629079; 25807530

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NARS2 gene.

• not_provided (270 variants)
• Inborn_genetic_diseases (70 variants)
• Combined_oxidative_phosphorylation_defect_type_24 (45 variants)
• not_specified (21 variants)
• NARS2-related_disorder (16 variants)
• Hearing_loss,_autosomal_recessive_94 (8 variants)
• Hepatoencephalopathy_due_to_combined_oxidative_phosphorylation_defect_type_1 (2 variants)
• Intellectual_disability (2 variants)
• NARS2-related_primary_mitochondrial_disorder (1 variants)
• Acute_refractory_chorea (1 variants)
• Mitochondrial_disease (1 variants)
• Sensorineural_hearing_loss_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NARS2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000024678.6. 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		1	1	53	3	58
missense	5	9	129	13	2	158
nonsense	4	3	2			9
start loss			1			1
frameshift	4	3	1			8
splice donor/acceptor (+/-2bp)	3	1	1			5
Total	16	17	135	66	5

Highest pathogenic variant AF is 0.0000954534

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NARS2	protein_coding	protein_coding	ENST00000281038	14	138913

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.11e-8	0.974	125708	0	39	125747	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.759	292	258	1.13	0.0000131	3108
Missense in Polyphen		86	95.418	0.9013		1127
Synonymous	-1.04	100	87.6	1.14	0.00000397	915
Loss of Function	2.12	16	28.2	0.568	0.00000152	331

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000630	0.000630
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000938	0.0000924
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.000272	0.000272
South Asian	0.0000674	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Combined oxidative phosphorylation deficiency 24 (COXPD24) [MIM:616239]: An autosomal recessive mitochondrial disorder with wide phenotypic variability. Some patients have a milder form affecting only skeletal muscle, whereas others may have a more severe disorder, reminiscent of Alpers syndrome. Alpers syndrome is a progressive neurodegenerative disorder that presents in infancy or early childhood and is characterized by diffuse degeneration of cerebral gray matter. {ECO:0000269|PubMed:25385316, ECO:0000269|PubMed:25629079}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:25807530}. Note=The disease may be caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Ectoderm Differentiation;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: 0.108

Intolerance Scores

• loftool: 0.527
• rvis_EVS: -0.29
• rvis_percentile_EVS: 33.42

Haploinsufficiency Scores

• pHI: 0.122
• hipred: N
• hipred_score: 0.492
• ghis: 0.602

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.759

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nars2

Gene ontology

• Biological process: asparaginyl-tRNA aminoacylation
• Cellular component: nucleoplasm;mitochondrion;mitochondrial matrix;cytosol
• Molecular function: nucleic acid binding;asparagine-tRNA ligase activity;ATP binding