6-87514472-G-T

Variant names:

• chr6-87514472-G-T
• rs562472225
• NM_020320.5:c.1678C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_020320.5(RARS2):​c.1678C>A​(p.Arg560Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R560C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARS2 NM_020320.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-87514471-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215071.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020320.5. 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.1678C>A	p.Arg560Ser	missense	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.1678C>A	p.Arg560Ser	missense	Exon 20 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.1153C>A	p.Arg385Ser	missense	Exon 20 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.1678C>A	p.Arg560Ser	missense	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000687437.1		c.1768C>A	p.Arg590Ser	missense	Exon 21 of 21	ENSP00000508968.1	A0A8I5KP51
	RARS2	ENST00000691725.1		c.1678C>A	p.Arg560Ser	missense	Exon 20 of 21	ENSP00000509453.1	A0A8I5KWC6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.73		Loss of MoRF binding (P = 0.0163)
MVP		0.89
MPC		0.53
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.57
Mutation Taster		=80/20	polymorphism

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: rs562472225; hg19: chr6-88224190;