6-87514311-C-CAA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_020320.5(RARS2):c.*101_*102insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00863 in 570,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: RARS2 NM_020320.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.613

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-87514311-C-CAA is Benign according to our data. Variant chr6-87514311-C-CAA is described in ClinVar as [Likely_benign]. Clinvar id is 3043976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0105 (4800/458272) while in subpopulation EAS AF= 0.0121 (238/19692). AF 95% confidence interval is 0.0108. There are 0 homozygotes in gnomad4_exome. There are 2540 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.*101_*102insTT		3_prime_UTR_variant	20/20	ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.*101_*102insTT		3_prime_UTR_variant	20/20	1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 121 AN: 112180 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000753

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0105 AC: 4800 AN: 458272 Hom.: 0 AF XY: 0.0103 AC XY: 2540 AN XY: 246448

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.00944

Gnomad4 EAS exome AF: 0.0121

Gnomad4 SAS exome AF: 0.00733

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00108 AC: 121 AN: 112210 Hom.: 0 Cov.: 0 AF XY: 0.00116 AC XY: 62 AN XY: 53432

Gnomad4 AFR AF: 0.000521

Gnomad4 AMR AF: 0.00339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000756

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RARS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5878032; hg19: chr6-88224029;