chr6-87521508-T-C

Position:

chr6-87521508-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

RARS2 (HGNC:):

RARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
RARS2	NM_020320.5 linkuse as main transcript	c.991A>G	p.Ile331Val	missense_variant	12/20	ENST00000369536.10	NP_064716.2	Q5T160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10 linkuse as main transcript	c.991A>G	p.Ile331Val	missense_variant	12/20	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

GnomAD3 exomes

AF:

0.0352

AC:

8831

AN:

250910

Hom.:

300

AF XY:

0.0365

AC XY:

4945

AN XY:

135644

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 SAS exome

AF:

0.0473

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

Gnomad4 AFR exome

AF:

0.00362

Gnomad4 AMR exome

AF:

0.0100

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.117

Gnomad4 SAS exome

AF:

0.0480

Gnomad4 FIN exome

AF:

0.0737

Gnomad4 NFE exome

AF:

0.0222

Gnomad4 OTH exome

AF:

0.0269

GnomAD4 genome

AF:

0.0252

AC:

3845

AN:

152288

Hom.:

115

Cov.:

AF XY:

0.0282

AC XY:

2103

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.0140

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.116

Gnomad4 SAS

AF:

0.0478

Gnomad4 FIN

AF:

0.0767

Gnomad4 NFE

AF:

0.0260

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0243

Hom.:

146

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pontocerebellar hypoplasia type 6

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

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

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

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over