Genetic Variant 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 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DARS2	NM_018122.5	MANE Select	c.1273G>A	p.Glu425Lys	missense	Exon 13 of 17	NP_060592.2
DARS2	NM_001365213.2		c.1273G>A	p.Glu425Lys	missense	Exon 13 of 14	NP_001352142.1
DARS2	NM_001365212.1		c.1192-2941G>A		intron	N/A	NP_001352141.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DARS2	ENST00000649689.2	MANE Select	c.1273G>A	p.Glu425Lys	missense	Exon 13 of 17	ENSP00000497569.1
DARS2	ENST00000647645.1		c.1210G>A	p.Glu404Lys	missense	Exon 12 of 16	ENSP00000497450.1
DARS2	ENST00000648458.1		c.1273G>A	p.Glu425Lys	missense	Exon 13 of 14	ENSP00000497874.1

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 v4.9

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

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.4

PhyloP100

1.2

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.80

REVEL

Benign

0.26

Sift

Benign

0.22

Sift4G

Benign

0.63

Polyphen

0.26

Vest4

0.15

MutPred

0.52

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over