chr6-87514311-C-CAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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
• Publications: 1 publications found

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]

RARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pontocerebellar hypoplasia type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350505.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	NM_020320.5	MANE Select	c.*100_*101dupTT		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001318785.2		c.*100_*101dupTT		3_prime_UTR	Exon 19 of 19	NP_001305714.1	H0UI22
	RARS2	NM_001350507.2		c.*100_*101dupTT		3_prime_UTR	Exon 21 of 21	NP_001337436.1	H0UI22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.*100_*101dupTT		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000685408.1		c.*100_*101dupTT		3_prime_UTR	Exon 21 of 21	ENSP00000509026.1	H0UI22
	RARS2	ENST00000689174.1		c.*100_*101dupTT		3_prime_UTR	Exon 20 of 20	ENSP00000510542.1	H0UI22

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 107 AN: 10456

American (AMR) AF: 0.00626 AC: 115 AN: 18368

Ashkenazi Jewish (ASJ) AF: 0.00944 AC: 120 AN: 12716

East Asian (EAS) AF: 0.0121 AC: 238 AN: 19692

South Asian (SAS) AF: 0.00733 AC: 363 AN: 49540

European-Finnish (FIN) AF: 0.0122 AC: 339 AN: 27802

Middle Eastern (MID) AF: 0.00975 AC: 15 AN: 1538

European-Non Finnish (NFE) AF: 0.0111 AC: 3282 AN: 296958

Other (OTH) AF: 0.0104 AC: 221 AN: 21202

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000521 AC: 15 AN: 28802

American (AMR) AF: 0.00339 AC: 39 AN: 11516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2778

East Asian (EAS) AF: 0.000756 AC: 3 AN: 3968

South Asian (SAS) AF: 0.00 AC: 0 AN: 3590

European-Finnish (FIN) AF: 0.00101 AC: 6 AN: 5962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00109 AC: 58 AN: 53254

Other (OTH) AF: 0.00 AC: 0 AN: 1478

Alfa AF: 0.00 Hom.: 171

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	RARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61

Splicing

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

Other links and lift over

dbSNP: rs5878032; hg19: chr6-88224029;