6-87530829-T-G

Variant names:

• chr6-87530829-T-G
• rs145499324
• NM_020320.5:c.726A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_020320.5(RARS2):​c.726A>C​(p.Gln242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q242Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: RARS2 NM_020320.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_020320.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25977293).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	NM_020320.5	MANE Select	c.726A>C	p.Gln242His	missense	Exon 9 of 20	NP_064716.2
	RARS2	NM_001350505.2		c.726A>C	p.Gln242His	missense	Exon 9 of 21	NP_001337434.1
	RARS2	NM_001350506.2		c.201A>C	p.Gln67His	missense	Exon 9 of 21	NP_001337435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.726A>C	p.Gln242His	missense	Exon 9 of 20	ENSP00000358549.5
	RARS2	ENST00000687437.1		c.726A>C	p.Gln242His	missense	Exon 9 of 21	ENSP00000508968.1
	RARS2	ENST00000691725.1		c.726A>C	p.Gln242His	missense	Exon 9 of 21	ENSP00000509453.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.58
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.030	D
Polyphen		0.29	B
Vest4		0.49
MutPred		0.47		Loss of helix (P = 0.0376)
MVP		0.70
MPC		0.36
ClinPred		0.71	D
GERP RS		-1.7
Varity_R		0.24
gMVP		0.48
Mutation Taster		=76/24	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: rs145499324; hg19: chr6-88240547;