NM_018122.5:c.59G>A

Variant names:

• chr1-173825288-G-A
• rs1162320028
• NM_018122.5:c.59G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018122.5(DARS2):​c.59G>A​(p.Arg20Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. R20M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049797297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.59G>A	p.Arg20Lys	missense_variant	Exon 1 of 17	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.59G>A	p.Arg20Lys	missense_variant	Exon 1 of 16		NP_001352141.1
DARS2	NM_001365213.2	c.59G>A	p.Arg20Lys	missense_variant	Exon 1 of 14		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.59G>A	p.Arg20Lys	missense_variant	Exon 1 of 17		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.0
DANN	Benign	0.56
DEOGEN2	Benign	0.023	T;.;.;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.47	.;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.050	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N;.;.;.;N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.16	N;.;.;.;.;.;.
REVEL	Benign	0.16
Sift	Benign	0.66	T;.;.;.;.;.;.
Sift4G	Benign	1.0	T;.;.;.;.;.;.
Polyphen		0.0	B;.;.;.;B;.;.
Vest4		0.12
MutPred		0.45		Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);Gain of methylation at R20 (P = 0.0238);
MVP		0.69
MPC		0.24
ClinPred		0.018	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1162320028; hg19: chr1-173794426;