rs145189950

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The ENST00000369536.10(RARS2):ā€‹c.888G>Cā€‹(p.Thr296=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,610,434 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T296T) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0012 ( 0 hom., cov: 32)
Exomes š‘“: 0.0011 ( 2 hom. )

Consequence

RARS2
ENST00000369536.10 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.621
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 6-87524643-C-G is Benign according to our data. Variant chr6-87524643-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138896.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=2}.
BP7
Synonymous conserved (PhyloP=-0.621 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RARS2NM_020320.5 linkuse as main transcriptc.888G>C p.Thr296= synonymous_variant 11/20 ENST00000369536.10 NP_064716.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RARS2ENST00000369536.10 linkuse as main transcriptc.888G>C p.Thr296= synonymous_variant 11/201 NM_020320.5 ENSP00000358549 P1

Frequencies

GnomAD3 genomes
AF:
0.00119
AC:
181
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.0173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00142
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00143
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00130
AC:
325
AN:
250892
Hom.:
0
AF XY:
0.00131
AC XY:
178
AN XY:
135646
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.0102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.00131
Gnomad NFE exome
AF:
0.00149
Gnomad OTH exome
AF:
0.000816
GnomAD4 exome
AF:
0.00106
AC:
1546
AN:
1458226
Hom.:
2
Cov.:
30
AF XY:
0.00112
AC XY:
815
AN XY:
725670
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.0123
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000429
Gnomad4 FIN exome
AF:
0.00119
Gnomad4 NFE exome
AF:
0.000916
Gnomad4 OTH exome
AF:
0.00164
GnomAD4 genome
AF:
0.00119
AC:
181
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.00112
AC XY:
83
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.0173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00142
Gnomad4 NFE
AF:
0.00143
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00208
Hom.:
0
Bravo
AF:
0.00105
EpiCase
AF:
0.00136
EpiControl
AF:
0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 28, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 08, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Pontocerebellar hypoplasia type 6 Uncertain:1Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Oct 24, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023RARS2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
0.61
DANN
Benign
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145189950; hg19: chr6-88234361; COSMIC: COSV65761112; API