rs3734908

chr6-87518806-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020320.5(RARS2):c.1305+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 1,613,090 control chromosomes in the GnomAD database, including 2,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (389 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1741 hom.)
• Consequence: RARS2 NM_020320.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.305

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-87518806-G-A is Benign according to our data. Variant chr6-87518806-G-A is described in ClinVar as [Benign]. Clinvar id is 261219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-87518806-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.1305+18C>T		intron_variant		ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.1305+18C>T		intron_variant		1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9666 AN: 152046 Hom.: 387 Cov.: 31

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0528

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0606

GnomAD3 exomes AF: 0.0424 AC: 10671 AN: 251424 Hom.: 292 AF XY: 0.0415 AC XY: 5633 AN XY: 135882

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0476

GnomAD4 exome AF: 0.0447 AC: 65273 AN: 1460926 Hom.: 1741 Cov.: 32 AF XY: 0.0438 AC XY: 31822 AN XY: 726814

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0387

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.0207

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0636 AC: 9674 AN: 152164 Hom.: 389 Cov.: 31 AF XY: 0.0612 AC XY: 4551 AN XY: 74394

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0526

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0151

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.0600

Alfa AF: 0.0521 Hom.: 45

Bravo AF: 0.0696

Asia WGS AF: 0.0280 AC: 98 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	-0.81
Cadd	Benign	2.3
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3734908; hg19: chr6-88228524;