Genetic Variant RARS2:c.*115G>C (chr6-87514298-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001350505.2(RARS2):c.1733G>C(p.Arg578Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000781 in 640,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R578H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

RARS2
NM_001350505.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0640

Publications

2 publications found

Variant links:

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

RARS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS2	NM_020320.5	MANE Select	c.*115G>C		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
RARS2	NM_001350505.2		c.1733G>C	p.Arg578Pro	missense	Exon 21 of 21	NP_001337434.1	A0A8I5KWC6
RARS2	NM_001350506.2		c.1208G>C	p.Arg403Pro	missense	Exon 21 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS2	ENST00000369536.10	TSL:1 MANE Select	c.*115G>C		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
RARS2	ENST00000691725.1		c.1733G>C	p.Arg578Pro	missense	Exon 21 of 21	ENSP00000509453.1	A0A8I5KWC6
RARS2	ENST00000693431.1		c.1208G>C	p.Arg403Pro	missense	Exon 21 of 21	ENSP00000509147.1	A0A8I5KPZ0

Frequencies

GnomAD3 genomes

AF:

0.0000284

AC:

AN:

140984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000200

AC:

AN:

499554

Hom.:

AF XY:

0.00

AC XY:

AN XY:

269402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11868

American (AMR)

AF:

0.00

AC:

AN:

21962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14762

East Asian (EAS)

AF:

0.00

AC:

AN:

23596

South Asian (SAS)

AF:

0.00

AC:

AN:

52554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1842

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

318106

Other (OTH)

AF:

0.0000412

AC:

AN:

24258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000284

AC:

AN:

140984

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

67702

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

37724

American (AMR)

AF:

0.00

AC:

AN:

13554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

4910

South Asian (SAS)

AF:

0.00

AC:

AN:

4464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65720

Other (OTH)

AF:

0.00

AC:

AN:

1866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.57

(source)

DANN

Benign

0.15

PhyloP100

-0.064

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over