DARS2

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

Basic information

Region (hg38): 1:173824653-173858808

Links

ENSG00000117593 ∙ NCBI:55157 ∙ OMIM:610956 ∙ HGNC:25538 ∙ Uniprot:Q6PI48 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Strong), mode of inheritance: AR
• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Definitive), mode of inheritance: AD
• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Strong), mode of inheritance: AR
• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Supportive), mode of inheritance: AR
• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Strong), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation	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	15326244; 17384640; 19592391; 21749991; 21815884; 22677571; 23065766; 23644316

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DARS2 gene.

• not provided (24 variants)
• Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (12 variants)
• 10 conditions (2 variants)
• Gait imbalance;Dysmetria;Gait ataxia (2 variants)
• Inborn genetic diseases (2 variants)
• Spastic ataxia (1 variants)
• DARS2-related disorder (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DARS2 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	37		40
missense	5	11	111	6	2	135
nonsense	9	3				12
start loss						0
frameshift	13	3				16
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2	5	1			8
splice region			5	10	3	18
non coding	2		14	70	43	129
Total	31	22	130	113	45

Highest pathogenic variant AF is 0.000315

Variants in DARS2

This is a list of pathogenic ClinVar variants found in the DARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-173824687-C-T		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Jan 13, 2018)
1-173824697-G-A		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Jan 12, 2018)
1-173824708-G-C		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Jan 12, 2018)
1-173824742-G-C		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Jan 13, 2018)
1-173825011-C-T		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Apr 27, 2017)
1-173825083-A-G		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Jan 12, 2018)
1-173825235-C-G			Pathogenic (Dec 02, 2021)
1-173825237-T-G		Inborn genetic diseases	Uncertain significance (Apr 28, 2023)
1-173825240-C-G		Inborn genetic diseases	Uncertain significance (Mar 30, 2021)
1-173825249-T-A		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Pathogenic (Dec 18, 2017)
1-173825258-T-C			Uncertain significance (Sep 08, 2020)
1-173825260-T-C			Uncertain significance (Jul 03, 2022)
1-173825273-C-T			Likely benign (Jan 06, 2023)
1-173825286-A-C		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Feb 13, 2018)
1-173825294-C-T		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (Dec 11, 2023)
1-173825301-G-T			Likely benign (May 29, 2023)
1-173825308-G-A			Uncertain significance (May 16, 2023)
1-173825313-T-C			Likely benign (Jul 07, 2023)
1-173825315-T-G		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Uncertain significance (-)
1-173825318-A-G			Uncertain significance (Oct 24, 2022)
1-173825320-A-G		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome • Inborn genetic diseases	Uncertain significance (Apr 11, 2023)
1-173825335-A-G			Uncertain significance (Sep 01, 2023)
1-173825336-GT-G		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Pathogenic (Mar 27, 2024)
1-173825340-A-G			Likely benign (Dec 14, 2023)
1-173825345-G-GGA		Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Pathogenic (Apr 03, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DARS2	protein_coding	protein_coding	ENST00000361951	17	34044

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.79e-13	0.888	125593	0	155	125748	0.000616

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.19	285	348	0.820	0.0000179	4203
Missense in Polyphen		83	117.09	0.70886		1328
Synonymous	0.962	108	121	0.889	0.00000581	1251
Loss of Function	1.97	25	38.2	0.655	0.00000210	451

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000680	0.000680
Ashkenazi Jewish	0.00218	0.00218
East Asian	0.000272	0.000272
Finnish	0.00171	0.00171
European (Non-Finnish)	0.000503	0.000501
Middle Eastern	0.000272	0.000272
South Asian	0.000229	0.000229
Other	0.00131	0.00130

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) [MIM:611105]: Autosomal recessive disease and is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. {ECO:0000269|PubMed:17384640}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);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: 0.172

Intolerance Scores

• loftool: 0.406
• rvis_EVS: 0.2
• rvis_percentile_EVS: 67.19

Haploinsufficiency Scores

• pHI: 0.365
• hipred: N
• hipred_score: 0.204
• ghis: 0.583

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.996

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dars2
• 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)

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;tRNA aminoacylation;mitochondrial asparaginyl-tRNA aminoacylation
• Cellular component: nucleus;mitochondrion;mitochondrial matrix
• Molecular function: tRNA binding;aspartate-tRNA ligase activity;protein binding;ATP binding;protein homodimerization activity;aspartate-tRNA(Asn) ligase activity