dbSNP rs121918211: DARS2:p.Glu425Lys (chr1-173850408-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018122.5(DARS2):c.1273G>A(p.Glu425Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. E425null) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

7 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

DARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1462912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 13 of 17	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365213.2 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 13 of 14		NP_001352142.1
DARS2	NM_001365212.1 link	c.1192-2941G>A		intron_variant	Intron 12 of 15		NP_001352141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 13 of 17		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251328

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.30

T;T;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

.;T;T;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.4

M;M;.;.

PhyloP100

1.2

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.80

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.22

T;.;.;.

Sift4G

Benign

0.63

T;.;.;.

Polyphen

0.26

B;B;.;.

Vest4

0.15

MutPred

0.52

Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);

MVP

0.88

MPC

0.28

ClinPred

0.21

GERP RS

4.8

Varity_R

0.17

gMVP

0.58

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over