Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6
The NM_020320.5(RARS2):c.1678C>T(p.Arg560Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,612,456 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560H) has been classified as Likely pathogenic.
RARS2 (HGNC:21406): (arginyl-tRNA synthetase 2, mitochondrial) This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
Verdict is Likely_benign. Variant got -3 ACMG points.
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr6-87514471-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215071.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}.
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.022638261).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-87514472-G-A is Benign according to our data. Variant chr6-87514472-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 766634.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 22, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jan 06, 2023
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27166760) -