GeneBe

1-173828312-T-TGGGGGG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018122.5(DARS2):​c.228-21_228-20insGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,932 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 27)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

DARS2
NM_018122.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.51

Publications

0 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS2NM_018122.5 linkc.228-21_228-20insGGGGGG intron_variant Intron 2 of 16 ENST00000649689.2 NP_060592.2
DARS2NM_001365212.1 linkc.228-21_228-20insGGGGGG intron_variant Intron 2 of 15 NP_001352141.1
DARS2NM_001365213.2 linkc.228-21_228-20insGGGGGG 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.228-21_228-20insGGGGGG intron_variant Intron 2 of 16 NM_018122.5 ENSP00000497569.1

Frequencies

GnomAD3 genomes
Cov.:
27
GnomAD4 exome
AF:
0.00000285
AC:
4
AN:
1401932
Hom.:
0
Cov.:
22
AF XY:
0.00000286
AC XY:
2
AN XY:
698264
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32282
American (AMR)
AF:
0.00
AC:
0
AN:
43874
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24638
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38084
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82006
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52158
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5542
European-Non Finnish (NFE)
AF:
0.00000375
AC:
4
AN:
1065646
Other (OTH)
AF:
0.00
AC:
0
AN:
57702
⚠️ 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: 0.263
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
2.5

Splicing

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

Publications

Other links and lift over

dbSNP: rs367543010; hg19: chr1-173797450; API