RARS2

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

Basic information

Region (hg38): 6:87513458-87590028

Previous symbols: [ "RARSL" ]

Links

ENSG00000146282 ∙ NCBI:57038 ∙ OMIM:611524 ∙ HGNC:21406 ∙ Uniprot:Q5T160 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pontocerebellar hypoplasia type 6 (Definitive), mode of inheritance: AR
• pontocerebellar hypoplasia type 6 (Strong), mode of inheritance: AR
• pontocerebellar hypoplasia type 6 (Strong), mode of inheritance: AR
• pontocerebellar hypoplasia type 6 (Strong), mode of inheritance: AR
• pontocerebellar hypoplasia type 6 (Supportive), mode of inheritance: AR
• complex neurodevelopmental disorder (Limited), mode of inheritance: AD
• pontocerebellar hypoplasia type 6 (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
Pontocerebellar hypoplasia, type 6	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	Neurologic	17847012; 20635367; 22569581; 25809939

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RARS2 gene.

• not provided (576 variants)
• Pontocerebellar hypoplasia type 6 (198 variants)
• not specified (60 variants)
• Inborn genetic diseases (31 variants)
• Pontoneocerebellar hypoplasia (16 variants)
• RARS2-related condition (3 variants)
• Congenital cerebellar hypoplasia (2 variants)
• Abnormal brain morphology (1 variants)
• Congenital disorder of glycosylation (1 variants)
• Severe intellectual deficiency (1 variants)
• Secondary microcephaly;Intellectual disability;Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RARS2 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			2	147	1	150
missense	1	13	104	8	4	130
nonsense	14	19				33
start loss	5	3				8
frameshift	24	37	2			63
inframe indel			3			3
splice donor/acceptor (+/-2bp)	5	42				47
splice region	1	1	9	40	3	54
non coding		1	5	105	41	152
Total	49	115	116	260	46

Highest pathogenic variant AF is 0.0000591

Variants in RARS2

This is a list of pathogenic ClinVar variants found in the RARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-87514172-G-A			Benign (Jun 26, 2018)
6-87514298-C-T			Benign (Jun 26, 2018)
6-87514311-CA-C			Benign (Aug 10, 2019)
6-87514311-C-CA		RARS2-related disorder	Benign (Mar 28, 2022)
6-87514311-C-CAA		RARS2-related disorder	Likely benign (Apr 29, 2020)
6-87514358-C-A			Likely benign (Jul 08, 2018)
6-87514414-T-C			Likely benign (Nov 25, 2023)
6-87514417-A-G		Inborn genetic diseases	Uncertain significance (Jan 26, 2022)
6-87514425-T-TA		not specified • Pontocerebellar hypoplasia type 6	Uncertain significance (Nov 11, 2013)
6-87514428-A-T			Likely benign (May 21, 2022)
6-87514432-G-A		not specified	Uncertain significance (Jan 03, 2022)
6-87514437-T-G			Likely benign (May 17, 2023)
6-87514442-G-A		Inborn genetic diseases • Pontocerebellar hypoplasia type 6	Uncertain significance (Jan 06, 2022)
6-87514446-T-C		not specified • Congenital disorder of glycosylation • Pontoneocerebellar hypoplasia • Pontocerebellar hypoplasia type 6	Benign/Likely benign (Feb 01, 2024)
6-87514458-G-C		Pontocerebellar hypoplasia type 6	Likely benign (Jun 04, 2023)
6-87514464-G-A			Likely benign (Jun 20, 2023)
6-87514471-C-A			Uncertain significance (Jul 20, 2022)
6-87514471-C-T		Pontocerebellar hypoplasia type 6	Conflicting classifications of pathogenicity (Nov 20, 2023)
6-87514472-G-A		Pontocerebellar hypoplasia type 6	Conflicting classifications of pathogenicity (Jan 22, 2024)
6-87514473-G-A			Likely benign (Jun 14, 2023)
6-87514475-C-T		Pontocerebellar hypoplasia type 6	Uncertain significance (Aug 14, 2020)
6-87514476-A-G			Likely benign (Apr 10, 2021)
6-87514496-T-C			Uncertain significance (Jun 10, 2021)
6-87514507-A-G			Likely benign (Apr 28, 2021)
6-87514508-TAAATC-T		not specified	Likely benign (Jan 31, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RARS2	protein_coding	protein_coding	ENST00000369536	20	75626

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.74e-14	0.844	125645	0	103	125748	0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0650	308	305	1.01	0.0000159	3780
Missense in Polyphen		101	118.72	0.85078		1392
Synonymous	-0.735	115	105	1.09	0.00000562	1068
Loss of Function	1.95	27	40.3	0.669	0.00000204	472

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000941	0.000941
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000653	0.000653
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000502	0.000501
Middle Eastern	0.000653	0.000653
South Asian	0.000359	0.000359
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Pontocerebellar hypoplasia 6 (PCH6) [MIM:611523]: A disorder characterized by an abnormally small cerebellum and brainstem, infantile encephalopathy, generalized hypotonia, lethargy and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition. {ECO:0000269|PubMed:17847012}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Prolinemia Type II;Prolidase Deficiency (PD);Arginine and Proline Metabolism;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);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: 0.123

Intolerance Scores

• loftool: 0.879
• rvis_EVS: -0.13
• rvis_percentile_EVS: 43.91

Haploinsufficiency Scores

• pHI: 0.504
• hipred: N
• hipred_score: 0.476
• ghis: 0.615

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.964

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rars2
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: rars2
• Affected structure: midbrain hindbrain boundary
• Phenotype tag: abnormal
• Phenotype quality: dorso-ventrally flattened

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;arginyl-tRNA aminoacylation;mitochondrial translation
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: RNA binding;arginine-tRNA ligase activity;ATP binding