rs1085307089
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_020320.5(RARS2):โc.189delโ(p.Gln64LysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (โ ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes ๐: 6.9e-7 ( 0 hom. )
Consequence
RARS2
NM_020320.5 frameshift
NM_020320.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.830
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARS2 | NM_020320.5 | c.189del | p.Gln64LysfsTer5 | frameshift_variant | 3/20 | ENST00000369536.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARS2 | ENST00000369536.10 | c.189del | p.Gln64LysfsTer5 | frameshift_variant | 3/20 | 1 | NM_020320.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
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33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251290Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135834
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459850Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726416
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pontocerebellar hypoplasia type 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at