chr6-87521508-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020320.5(RARS2):c.991A>G(p.Ile331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,648 control chromosomes in the GnomAD database, including 986 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 115 hom., cov: 32)

Exomes 𝑓: 0.027 ( 871 hom. )

Consequence

RARS2
NM_020320.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.88

Publications

24 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=0.0019848347).

BP6

Variant 6-87521508-T-C is Benign according to our data. Variant chr6-87521508-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5 link	c.991A>G	p.Ile331Val	missense_variant	Exon 12 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.991A>G	p.Ile331Val	missense_variant	Exon 12 of 20	1	NM_020320.5	ENSP00000358549.5		Q5T160

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3844

AN:

152170

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.0476

Gnomad FIN

AF:

0.0767

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0260

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0352

AC:

8831

AN:

250910

AF XY:

0.0365

show subpopulations

Gnomad AFR exome

AF:

0.00377

Gnomad AMR exome

AF:

0.00920

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.0755

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0330

GnomAD4 exome

AF:

0.0273

AC:

39904

AN:

1459360

Hom.:

871

Cov.:

AF XY:

0.0284

AC XY:

20648

AN XY:

726096

show subpopulations

African (AFR)

AF:

0.00362

AC:

121

AN:

33416

American (AMR)

AF:

0.0100

AC:

448

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

297

AN:

26100

East Asian (EAS)

AF:

0.117

AC:

4632

AN:

39546

South Asian (SAS)

AF:

0.0480

AC:

4139

AN:

86174

European-Finnish (FIN)

AF:

0.0737

AC:

3922

AN:

53236

Middle Eastern (MID)

AF:

0.0205

AC:

118

AN:

5756

European-Non Finnish (NFE)

AF:

0.0222

AC:

24603

AN:

1110140

Other (OTH)

AF:

0.0269

AC:

1624

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1653

3306

4958

6611

8264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.0252

AC:

3845

AN:

152288

Hom.:

115

Cov.:

AF XY:

0.0282

AC XY:

2103

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00346

AC:

144

AN:

41564

American (AMR)

AF:

0.0140

AC:

215

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3470

East Asian (EAS)

AF:

0.116

AC:

601

AN:

5182

South Asian (SAS)

AF:

0.0478

AC:

231

AN:

4832

European-Finnish (FIN)

AF:

0.0767

AC:

812

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0260

AC:

1767

AN:

68024

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

181

361

542

722

903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0234

Hom.:

200

Bravo

AF:

0.0185

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0358

AC:

4342

Asia WGS

AF:

0.0660

AC:

230

AN:

3474

EpiCase

AF:

0.0195

EpiControl

AF:

0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2014

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. -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pontocerebellar hypoplasia type 6

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

Eigen

Benign

0.0015

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.70

PhyloP100

2.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.53

REVEL

Benign

0.050

Sift

Benign

0.25

Sift4G

Benign

0.32

Polyphen

0.22

Vest4

0.067

MPC

0.10

ClinPred

0.040

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.42

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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