1-173830763-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_018122.5(DARS2):c.396+2T>G variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000124 in 1,611,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DARS2
NM_018122.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 5.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05263158 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 4, new splice context is: gagGTagtt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-173830763-T-G is Pathogenic according to our data. Variant chr1-173830763-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449386.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}. Variant chr1-173830763-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.396+2T>G	splice_donor_variant, intron_variant	Intron 4 of 16	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.396+2T>G	splice_donor_variant, intron_variant	Intron 4 of 15		NP_001352141.1
DARS2	NM_001365213.2 link	c.396+2T>G	splice_donor_variant, intron_variant	Intron 4 of 13		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.396+2T>G		splice_donor_variant, intron_variant	Intron 4 of 16		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251456

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459596

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:4

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 strong, PS4 supporting, PM2 moderated, PM3 supporting -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.396+2T>G variant in DARS2 has been reported, in the compound heterozygous state, in one individual with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640), but has been identified in 0.03% (15/59980) of Admixed chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759123043). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 449386) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is located in the 5' splice region. Computational tools predict both an in-frame and out-of-frame cryptic splice site, providing evidence that this variant may escape NMD or lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. Loss of function of the DARS2 gene is an established disease mechanism in autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3 (Richards 2015). -

not provided

Pathogenic:1Uncertain:1

Jan 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31589614, 17384640) -

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the DARS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DARS2 are known to be pathogenic (PMID: 17384640, 24566671). This variant is present in population databases (rs759123043, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (PMID: 17384640). This variant is also known as 396+2T>G. ClinVar contains an entry for this variant (Variation ID: 449386). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Aug 12, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.396+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 4 of the DARS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (9/282862) total alleles studied. The c.396+2T>G alteration has been identified in the compound heterozygous state with a second DARS2 alteration (c.228-15C>A) in one individual with leukoencephalopathy with brain stem and spinal cord involvement with lactate elevation (LBSL) (Scheper, 2007). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.95

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 2

DS_DL_spliceai

0.99

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over