rs6900057

chr6-87564251-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020320.5(RARS2):c.111-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,532,826 control chromosomes in the GnomAD database, including 2,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (547 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1839 hom.)
• Consequence: RARS2 NM_020320.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.20

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 -16 ACMG points.

• BP6: Variant 6-87564251-A-C is Benign according to our data. Variant chr6-87564251-A-C is described in ClinVar as [Benign]. Clinvar id is 261218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-87564251-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.111-19T>G		intron_variant		ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.111-19T>G		intron_variant		1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10938 AN: 152172 Hom.: 547 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0712

GnomAD3 exomes AF: 0.0446 AC: 11125 AN: 249614 Hom.: 363 AF XY: 0.0430 AC XY: 5802 AN XY: 135030

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0461 AC: 63682 AN: 1380536 Hom.: 1839 Cov.: 24 AF XY: 0.0450 AC XY: 31137 AN XY: 691880

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0400

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.0206

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0494

GnomAD4 genome AF: 0.0719 AC: 10945 AN: 152290 Hom.: 547 Cov.: 33 AF XY: 0.0696 AC XY: 5184 AN XY: 74478

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.0146

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0480

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0554 Hom.: 283

Bravo AF: 0.0793

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Pontocerebellar hypoplasia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6900057; hg19: chr6-88273969;