rs367543010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_018122.5(DARS2):c.228-21_228-20insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,547,144 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 24 hom., cov: 27)

Exomes 𝑓: 0.0033 ( 28 hom. )

Consequence

DARS2
NM_018122.5 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.51

Publications

1 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 -16 ACMG points.

BP6

Variant 1-173828312-T-TC is Benign according to our data. Variant chr1-173828312-T-TC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 559195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.228-21_228-20insC	intron_variant	Intron 2 of 16	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.228-21_228-20insC	intron_variant	Intron 2 of 15		NP_001352141.1
DARS2	NM_001365213.2 link	c.228-21_228-20insC	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.228-21_228-20insC		intron_variant	Intron 2 of 16		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

AF:

0.00664

AC:

992

AN:

149298

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.0108

Gnomad EAS

AF:

0.0167

Gnomad SAS

AF:

0.0624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.000905

Gnomad OTH

AF:

0.00341

GnomAD2 exomes

AF:

0.00591

AC:

1431

AN:

242088

AF XY:

0.00708

show subpopulations

Gnomad AFR exome

AF:

0.00607

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.00385

Gnomad EAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.000939

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00329

AC:

4593

AN:

1397728

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

2939

AN XY:

695708

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00500

AC:

161

AN:

32178

American (AMR)

AF:

0.00181

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00454

AC:

111

AN:

24462

East Asian (EAS)

AF:

0.00737

AC:

279

AN:

37864

South Asian (SAS)

AF:

0.0331

AC:

2660

AN:

80434

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

52020

Middle Eastern (MID)

AF:

0.00488

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.000970

AC:

1032

AN:

1063992

Other (OTH)

AF:

0.00323

AC:

186

AN:

57516

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

296

593

889

1186

1482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.00667

AC:

996

AN:

149416

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

574

AN XY:

72968

show subpopulations

African (AFR)

AF:

0.0119

AC:

481

AN:

40388

American (AMR)

AF:

0.00221

AC:

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

AN:

3440

East Asian (EAS)

AF:

0.0167

AC:

AN:

5084

South Asian (SAS)

AF:

0.0625

AC:

290

AN:

4642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000905

AC:

AN:

67432

Other (OTH)

AF:

0.00338

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00359

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DARS2: BS1, BS2 -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31664448) -

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

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over