1-173825308-G-C

Variant names:

• chr1-173825308-G-C
• rs1298680455
• NM_018122.5:c.79G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018122.5(DARS2):​c.79G>C​(p.Gly27Arg) 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. G27S) 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: -0.273

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08275595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.79G>C	p.Gly27Arg	missense_variant	Exon 1 of 17	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.79G>C	p.Gly27Arg	missense_variant	Exon 1 of 16		NP_001352141.1
DARS2	NM_001365213.2	c.79G>C	p.Gly27Arg	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.79G>C	p.Gly27Arg	missense_variant	Exon 1 of 17		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.6
DANN	Benign	0.88
DEOGEN2	Benign	0.045	T;.;.;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.51	.;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.083	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.040	N;.;.;.;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.10	T;.;.;.;.;.;.
Sift4G	Uncertain	0.038	D;.;.;.;.;.;.
Polyphen		0.0020	B;.;.;.;B;.;.
Vest4		0.17
MutPred		0.51		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.72
MPC		0.28
ClinPred		0.049	T
GERP RS		-1.3
Varity_R		0.053
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1298680455; hg19: chr1-173794446;