chr6-87530852-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.810

Publications

19 publications found

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]

RARS2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
pontocerebellar hypoplasia type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 130098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 104 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5 link	c.703G>A	p.Val235Met	missense_variant	Exon 9 of 20	ENST00000369536.10	NP_064716.2	Q5T160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10 link	c.703G>A	p.Val235Met	missense_variant	Exon 9 of 20	1	NM_020320.5	ENSP00000358549.5		Q5T160

Frequencies

GnomAD3 genomes

AF:

0.0302

AC:

4590

AN:

152208

Hom.:

104

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0323

AC:

8110

AN:

251472

AF XY:

0.0342

show subpopulations

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 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.:

AF XY:

0.0431

AC XY:

31367

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00654

AC:

219

AN:

33480

American (AMR)

AF:

0.0166

AC:

742

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26134

East Asian (EAS)

AF:

0.000605

AC:

AN:

39694

South Asian (SAS)

AF:

0.0419

AC:

3613

AN:

86258

European-Finnish (FIN)

AF:

0.0503

AC:

2687

AN:

53420

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0478

AC:

53185

AN:

1111990

Other (OTH)

AF:

0.0370

AC:

2235

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3845

7690

11535

15380

19225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2016

4032

6048

8064

10080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0301

AC:

4586

AN:

152326

Hom.:

104

Cov.:

AF XY:

0.0302

AC XY:

2250

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00813

AC:

338

AN:

41570

American (AMR)

AF:

0.0263

AC:

403

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0391

AC:

189

AN:

4828

European-Finnish (FIN)

AF:

0.0480

AC:

509

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0446

AC:

3034

AN:

68030

Other (OTH)

AF:

0.0284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

223

447

670

894

1117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0376

Hom.:

453

Bravo

AF:

0.0262

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0527

AC:

203

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0321

AC:

3894

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0385

EpiControl

AF:

0.0364

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 6

Benign:4

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 06, 2012

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RARS2-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.088

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.011

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

-0.81

PrimateAI

Benign

0.20

PROVEAN

Benign

0.17

REVEL

Benign

0.068

Sift

Benign

0.088

Sift4G

Benign

0.083

Polyphen

0.0

Vest4

0.21

MPC

0.11

ClinPred

0.0012

GERP RS

-5.6

Varity_R

0.033

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over