chr1-173828321-C-G

Variant summary

Our verdict is Benign. Variant got -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

2
Splicing: ADA: 0.001504
2

Clinical Significance

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

Conservation

PhyloP100: -0.138
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 137070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-173828321-C-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS2NM_018122.5 linkc.228-12C>G intron_variant Intron 2 of 16 ENST00000649689.2 NP_060592.2 Q6PI48Q9H9J7
DARS2NM_001365212.1 linkc.228-12C>G intron_variant Intron 2 of 15 NP_001352141.1
DARS2NM_001365213.2 linkc.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
DARS2ENST00000649689.2 linkc.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.:
30
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
GnomAD3 exomes
AF:
0.0219
AC:
5479
AN:
250472
Hom.:
656
AF XY:
0.0165
AC XY:
2240
AN XY:
135512
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 SAS exome
AF:
0.000852
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.:
30
AF XY:
0.00958
AC XY:
5888
AN XY:
614336
show subpopulations
Gnomad4 AFR exome
AF:
0.305
Gnomad4 AMR exome
AF:
0.0172
Gnomad4 ASJ exome
AF:
0.0300
Gnomad4 EAS exome
AF:
0.000631
Gnomad4 SAS exome
AF:
0.00105
Gnomad4 FIN exome
AF:
0.0000219
Gnomad4 NFE exome
AF:
0.00132
Gnomad4 OTH exome
AF:
0.0258
GnomAD4 genome
AF:
0.0788
AC:
11632
AN:
147590
Hom.:
1478
Cov.:
30
AF XY:
0.0768
AC XY:
5522
AN XY:
71922
show subpopulations
Gnomad4 AFR
AF:
0.266
Gnomad4 AMR
AF:
0.0349
Gnomad4 ASJ
AF:
0.0256
Gnomad4 EAS
AF:
0.000212
Gnomad4 SAS
AF:
0.00114
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00144
Gnomad4 OTH
AF:
0.0623
Alfa
AF:
0.00793
Hom.:
15
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
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

- -

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

- -

-
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

- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Benign:4
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

- -

Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.63
DANN
Benign
0.73

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

LitVar

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

Other links and lift over

dbSNP: rs9425753; hg19: chr1-173797459; API