Variant chr6-87514446-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020320.5(RARS2):c.1704A>G(p.Lys568=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,611,220 control chromosomes in the GnomAD database, including 8,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1206 hom., cov: 32)

Exomes 𝑓: 0.10 ( 7754 hom. )

Consequence

RARS2
NM_020320.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.859

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 6-87514446-T-C is Benign according to our data. Variant chr6-87514446-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-87514446-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.859 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5 linkuse as main transcript	c.1704A>G	p.Lys568=	synonymous_variant	20/20	ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10 linkuse as main transcript	c.1704A>G	p.Lys568=	synonymous_variant	20/20	1	NM_020320.5	P1

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18348

AN:

152114

Hom.:

1198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.0908

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0972

Gnomad OTH

AF:

0.117

GnomAD3 exomes

AF:

0.110

AC:

27683

AN:

251374

Hom.:

1626

AF XY:

0.108

AC XY:

14647

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.163

Gnomad AMR exome

AF:

0.118

Gnomad ASJ exome

AF:

0.0899

Gnomad EAS exome

AF:

0.168

Gnomad SAS exome

AF:

0.0984

Gnomad FIN exome

AF:

0.0980

Gnomad NFE exome

AF:

0.0981

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.100

AC:

146342

AN:

1458988

Hom.:

7754

Cov.:

AF XY:

0.0998

AC XY:

72462

AN XY:

725992

show subpopulations

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.0896

Gnomad4 EAS exome

AF:

0.155

Gnomad4 SAS exome

AF:

0.102

Gnomad4 FIN exome

AF:

0.0995

Gnomad4 NFE exome

AF:

0.0953

Gnomad4 OTH exome

AF:

0.106

GnomAD4 genome

AF:

0.121

AC:

18392

AN:

152232

Hom.:

1206

Cov.:

AF XY:

0.121

AC XY:

8971

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.160

Gnomad4 AMR

AF:

0.133

Gnomad4 ASJ

AF:

0.0908

Gnomad4 EAS

AF:

0.155

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.101

Gnomad4 NFE

AF:

0.0973

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.101

Hom.:

1905

Bravo

AF:

0.128

Asia WGS

AF:

0.151

AC:

527

AN:

3478

EpiCase

AF:

0.0938

EpiControl

AF:

0.0963

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Pontocerebellar hypoplasia type 6

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Congenital disorder of glycosylation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pontoneocerebellar hypoplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.5

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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