6-87546374-T-G

Variant names:

• chr6-87546374-T-G
• rs7757636
• NM_020320.5:c.452-675A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RARS2	NM_020320.5	c.452-675A>C		intron_variant	Intron 6 of 19	ENST00000369536.10	NP_064716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10	c.452-675A>C		intron_variant	Intron 6 of 19	1	NM_020320.5	ENSP00000358549.5

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

African (AFR) AF: 0.844 AC: 35043 AN: 41512

American (AMR) AF: 0.688 AC: 10500 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1708 AN: 3470

East Asian (EAS) AF: 0.563 AC: 2913 AN: 5174

South Asian (SAS) AF: 0.569 AC: 2740 AN: 4816

European-Finnish (FIN) AF: 0.519 AC: 5493 AN: 10580

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36249 AN: 67958

Other (OTH) AF: 0.619 AC: 1308 AN: 2112

Alfa AF: 0.564 Hom.: 41295

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
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7757636; hg19: chr6-88256092;