rs6900057

Variant names:

• chr6-87564251-A-C
• rs6900057
• NM_020320.5:c.111-19T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020320.5(RARS2):​c.111-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,532,826 control chromosomes in the GnomAD database, including 2,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (547 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1839 hom.)
• Consequence: RARS2 NM_020320.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.20
• Publications: 8 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 -16 ACMG points.

• BP6: Variant 6-87564251-A-C is Benign according to our data. Variant chr6-87564251-A-C is described in ClinVar as Benign. ClinVar VariationId is 261218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5	c.111-19T>G		intron_variant	Intron 2 of 19	ENST00000369536.10	NP_064716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10	c.111-19T>G		intron_variant	Intron 2 of 19	1	NM_020320.5	ENSP00000358549.5

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10938 AN: 152172 Hom.: 547 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0712

GnomAD2 exomes AF: 0.0446 AC: 11125 AN: 249614 AF XY: 0.0430

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0461 AC: 63682 AN: 1380536 Hom.: 1839 Cov.: 24 AF XY: 0.0450 AC XY: 31137 AN XY: 691880

African (AFR) AF: 0.149 AC: 4715 AN: 31710

American (AMR) AF: 0.0400 AC: 1784 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 606 AN: 25668

East Asian (EAS) AF: 0.0206 AC: 808 AN: 39274

South Asian (SAS) AF: 0.0204 AC: 1721 AN: 84558

European-Finnish (FIN) AF: 0.0229 AC: 1205 AN: 52646

Middle Eastern (MID) AF: 0.0525 AC: 295 AN: 5624

European-Non Finnish (NFE) AF: 0.0478 AC: 49692 AN: 1038708

Other (OTH) AF: 0.0494 AC: 2856 AN: 57786

GnomAD4 genome AF: 0.0719 AC: 10945 AN: 152290 Hom.: 547 Cov.: 33 AF XY: 0.0696 AC XY: 5184 AN XY: 74478

African (AFR) AF: 0.146 AC: 6055 AN: 41538

American (AMR) AF: 0.0546 AC: 835 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.0146 AC: 76 AN: 5192

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4828

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0480 AC: 3262 AN: 68028

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.0585 Hom.: 438

Bravo AF: 0.0793

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pontocerebellar hypoplasia type 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.58
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 17

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

Other links and lift over

dbSNP: rs6900057; hg19: chr6-88273969;