6-87546374-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020320.5(RARS2):c.452-675A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 152,098 control chromosomes in the GnomAD database, including 32,229 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (32229 hom., cov: 32)
• Consequence: RARS2 NM_020320.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.452-675A>C		intron_variant		ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.452-675A>C		intron_variant		1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96551 AN: 151980 Hom.: 32171 Cov.: 32

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.616

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.636 AC: 96674 AN: 152098 Hom.: 32229 Cov.: 32 AF XY: 0.634 AC XY: 47117 AN XY: 74346

Gnomad4 AFR AF: 0.844

Gnomad4 AMR AF: 0.688

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.619

Alfa AF: 0.552 Hom.: 30875

Bravo AF: 0.660

Asia WGS AF: 0.639 AC: 2221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.30
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7757636; hg19: chr6-88256092;