6-87514298-C-T

Variant names:

• chr6-87514298-C-T
• rs4615353
• NM_020320.5:c.*115G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001350505.2(RARS2):​c.1733G>A​(p.Arg578His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 639,874 control chromosomes in the GnomAD database, including 3,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1151 hom., cov: 28)
  • Exomes 𝑓: 0.090 (2339 hom.)
• Consequence: RARS2 NM_001350505.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0640
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-87514298-C-T is Benign according to our data. Variant chr6-87514298-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

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.*115G>A		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.1733G>A	p.Arg578His	missense	Exon 21 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.1208G>A	p.Arg403His	missense	Exon 21 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.*115G>A		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000691725.1		c.1733G>A	p.Arg578His	missense	Exon 21 of 21	ENSP00000509453.1	A0A8I5KWC6
	RARS2	ENST00000693431.1		c.1208G>A	p.Arg403His	missense	Exon 21 of 21	ENSP00000509147.1	A0A8I5KPZ0

Frequencies

GnomAD3 genomes AF: 0.127 AC: 17862 AN: 140860 Hom.: 1143 Cov.: 28

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.0897 AC: 44730 AN: 498926 Hom.: 2339 AF XY: 0.0898 AC XY: 24160 AN XY: 269062

African (AFR) AF: 0.140 AC: 1662 AN: 11852

American (AMR) AF: 0.113 AC: 2487 AN: 21930

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 1144 AN: 14744

East Asian (EAS) AF: 0.138 AC: 3249 AN: 23556

South Asian (SAS) AF: 0.0956 AC: 5021 AN: 52524

European-Finnish (FIN) AF: 0.0858 AC: 2623 AN: 30556

Middle Eastern (MID) AF: 0.0977 AC: 180 AN: 1842

European-Non Finnish (NFE) AF: 0.0822 AC: 26101 AN: 317684

Other (OTH) AF: 0.0934 AC: 2263 AN: 24238

GnomAD4 genome AF: 0.127 AC: 17905 AN: 140948 Hom.: 1151 Cov.: 28 AF XY: 0.129 AC XY: 8713 AN XY: 67740

African (AFR) AF: 0.169 AC: 6381 AN: 37772

American (AMR) AF: 0.147 AC: 1987 AN: 13558

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 312 AN: 3416

East Asian (EAS) AF: 0.160 AC: 781 AN: 4890

South Asian (SAS) AF: 0.111 AC: 496 AN: 4452

European-Finnish (FIN) AF: 0.124 AC: 1010 AN: 8136

Middle Eastern (MID) AF: 0.134 AC: 36 AN: 268

European-Non Finnish (NFE) AF: 0.0997 AC: 6547 AN: 65674

Other (OTH) AF: 0.128 AC: 241 AN: 1886

Alfa AF: 0.0427 Hom.: 40

Bravo AF: 0.128

Asia WGS AF: 0.152 AC: 528 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.19
PhyloP100		-0.064
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4615353; hg19: chr6-88224016;