6-87520236-CTT-CTTT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000369536.10(RARS2):c.1055dupA(p.His353AlafsTer15) 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 1,459,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
RARS2
ENST00000369536.10 frameshift
ENST00000369536.10 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.110
Publications
4 publications found
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]
RARS2 Gene-Disease associations (from GenCC):
- mitochondrial diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- pontocerebellar hypoplasia type 6Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
- complex neurodevelopmental disorderInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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;
PP5
Variant 6-87520236-C-CT is Pathogenic according to our data. Variant chr6-87520236-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 1970672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000369536.10. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RARS2 | NM_020320.5 | MANE Select | c.1055dupA | p.His353AlafsTer15 | frameshift | Exon 13 of 20 | NP_064716.2 | ||
| RARS2 | NM_001350505.2 | c.1055dupA | p.His353AlafsTer15 | frameshift | Exon 13 of 21 | NP_001337434.1 | |||
| RARS2 | NM_001350506.2 | c.530dupA | p.His178AlafsTer15 | frameshift | Exon 13 of 21 | NP_001337435.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RARS2 | ENST00000369536.10 | TSL:1 MANE Select | c.1055dupA | p.His353AlafsTer15 | frameshift | Exon 13 of 20 | ENSP00000358549.5 | ||
| RARS2 | ENST00000687437.1 | c.1055dupA | p.His353AlafsTer15 | frameshift | Exon 13 of 21 | ENSP00000508968.1 | |||
| RARS2 | ENST00000691725.1 | c.1055dupA | p.His353AlafsTer15 | frameshift | Exon 13 of 21 | ENSP00000509453.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250850 AF XY: 0.00000738 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
250850
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459748Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726296 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1459748
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
726296
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33438
American (AMR)
AF:
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26120
East Asian (EAS)
AF:
AC:
0
AN:
39664
South Asian (SAS)
AF:
AC:
1
AN:
86208
European-Finnish (FIN)
AF:
AC:
0
AN:
53058
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1110442
Other (OTH)
AF:
AC:
0
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
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0
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
1
-
-
Pontocerebellar hypoplasia type 6 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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