1-173838207-G-C

Position:

• chr1-173838207-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_018122.5(DARS2):​c.788G>C​(p.Arg263Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R263Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

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]

DARS2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-173838207-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1060.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DARS2	NM_018122.5	c.788G>C	p.Arg263Pro	missense_variant	9/17	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.788G>C	p.Arg263Pro	missense_variant	9/16		NP_001352141.1
DARS2	NM_001365213.2	c.788G>C	p.Arg263Pro	missense_variant	9/14		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.788G>C	p.Arg263Pro	missense_variant	9/17		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;D;.;.
Vest4		0.97
MutPred		0.84		Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.92

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: rs121918207; hg19: chr1-173807345;