6-87514311-C-CAA

Variant names:

• chr6-87514311-C-CAA
• rs5878032
• NM_020320.5:c.*100_*101dupTT

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_001350505.2(RARS2):​c.1723-5_1723-4dupTT variant causes a splice region, intron 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: RARS2 NM_001350505.2 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided 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 -3 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 no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00108 (121/112210) while in subpopulation AMR AF= 0.00339 (39/11516). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5	c.*100_*101dupTT		3_prime_UTR_variant	Exon 20 of 20	ENST00000369536.10	NP_064716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536	c.*100_*101dupTT		3_prime_UTR_variant	Exon 20 of 20	1	NM_020320.5	ENSP00000358549.5

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: no assertion criteria provided

Submissions by phenotype

RARS2-related disorder Benign:1

Apr 29, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;