6-87514446-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.859

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 -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	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	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.: 32

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

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.: 31 AF XY: 0.0998 AC XY: 72462 AN XY: 725992

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.: 32 AF XY: 0.121 AC XY: 8971 AN XY: 74442

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Pontocerebellar hypoplasia type 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
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. -

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

Other links and lift over

dbSNP: rs8802; hg19: chr6-88224164; COSMIC: COSV65760606; COSMIC: COSV65760606;