rs35862137

chr6-87530852-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020320.5(RARS2):c.703G>A(p.Val235Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,614,188 control chromosomes in the GnomAD database, including 1,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V235V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (104 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1591 hom.)
• Consequence: RARS2 NM_020320.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.810

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029790401).
• BP6: Variant 6-87530852-C-T is Benign according to our data. Variant chr6-87530852-C-T is described in ClinVar as [Benign]. Clinvar id is 130098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-87530852-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0301 (4586/152326) while in subpopulation NFE AF= 0.0446 (3034/68030). AF 95% confidence interval is 0.0433. There are 104 homozygotes in gnomad4. There are 2250 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.703G>A	p.Val235Met	missense_variant	9/20	ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.703G>A	p.Val235Met	missense_variant	9/20	1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4590 AN: 152208 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.00815

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0480

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0323 AC: 8110 AN: 251472 Hom.: 187 AF XY: 0.0342 AC XY: 4642 AN XY: 135908

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0424

Gnomad FIN exome AF: 0.0494

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0432 AC: 63117 AN: 1461862 Hom.: 1591 Cov.: 32 AF XY: 0.0431 AC XY: 31367 AN XY: 727240

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0301 AC: 4586 AN: 152326 Hom.: 104 Cov.: 33 AF XY: 0.0302 AC XY: 2250 AN XY: 74492

Gnomad4 AFR AF: 0.00813

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0391

Gnomad4 FIN AF: 0.0480

Gnomad4 NFE AF: 0.0446

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0387 Hom.: 235

Bravo AF: 0.0262

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0321 AC: 3894

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0364

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 6 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2013	This 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 06, 2012	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

RARS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.088
Dann	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.068
Sift	Benign	0.088	T
Sift4G	Benign	0.083	T
Polyphen		0.0	B
Vest4		0.21
MPC		0.11
ClinPred		0.0012	T
GERP RS		-5.6
Varity_R		0.033
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs35862137; hg19: chr6-88240570; COSMIC: COSV65762051;