1-173828321-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018122.5(DARS2):c.228-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,370,752 control chromosomes in the GnomAD database, including 3,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 1478 hom., cov: 30)

Exomes 𝑓: 0.011 ( 1524 hom. )

Consequence

DARS2
NM_018122.5 intron

Scores

Splicing: ADA: 0.001504

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.138

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 1-173828321-C-G is Benign according to our data. Variant chr1-173828321-C-G is described in ClinVar as Benign. ClinVar VariationId is 137070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.228-12C>G	intron_variant	Intron 2 of 16	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.228-12C>G	intron_variant	Intron 2 of 15		NP_001352141.1
DARS2	NM_001365213.2 link	c.228-12C>G	intron_variant	Intron 2 of 13		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.228-12C>G		intron_variant	Intron 2 of 16		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

AF:

0.0786

AC:

11595

AN:

147460

Hom.:

1474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0350

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.000211

Gnomad SAS

AF:

0.00160

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0132

Gnomad NFE

AF:

0.00145

Gnomad OTH

AF:

0.0629

GnomAD2 exomes

AF:

0.0219

AC:

5479

AN:

250472

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0108

AC:

13234

AN:

1223162

Hom.:

1524

Cov.:

AF XY:

0.00958

AC XY:

5888

AN XY:

614336

show subpopulations

African (AFR)

AF:

0.305

AC:

9179

AN:

30090

American (AMR)

AF:

0.0172

AC:

718

AN:

41816

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

608

AN:

20288

East Asian (EAS)

AF:

0.000631

AC:

AN:

30118

South Asian (SAS)

AF:

0.00105

AC:

AN:

81728

European-Finnish (FIN)

AF:

0.0000219

AC:

AN:

45708

Middle Eastern (MID)

AF:

0.0295

AC:

143

AN:

4852

European-Non Finnish (NFE)

AF:

0.00132

AC:

1212

AN:

919410

Other (OTH)

AF:

0.0258

AC:

1268

AN:

49152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

Heterozygous variant carriers

402

804

1205

1607

2009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0788

AC:

11632

AN:

147590

Hom.:

1478

Cov.:

AF XY:

0.0768

AC XY:

5522

AN XY:

71922

show subpopulations

African (AFR)

AF:

0.266

AC:

10799

AN:

40654

American (AMR)

AF:

0.0349

AC:

513

AN:

14708

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3396

East Asian (EAS)

AF:

0.000212

AC:

AN:

4728

South Asian (SAS)

AF:

0.00114

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9792

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

66714

Other (OTH)

AF:

0.0623

AC:

127

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.583

Heterozygous variant carriers

353

706

1059

1412

1765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00793

Hom.:

Bravo

AF:

0.0878

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28097321, 23065766, 27884173, 21427441) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 16, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Benign:4

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: BS1,BS2 -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.63

(source)

DANN

Benign

0.73

PhyloP100

-0.14

Mutation Taster

=27/73

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.050

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over