rs9425753
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_018122.5(DARS2):c.228-12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,370,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_018122.5 intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DARS2 | NM_018122.5 | c.228-12C>A | intron_variant | Intron 2 of 16 | ENST00000649689.2 | NP_060592.2 | ||
DARS2 | NM_001365212.1 | c.228-12C>A | intron_variant | Intron 2 of 15 | NP_001352141.1 | |||
DARS2 | NM_001365213.2 | c.228-12C>A | intron_variant | Intron 2 of 13 | NP_001352142.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000136 AC: 2AN: 147476Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250472Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135512
GnomAD4 exome AF: 0.0000213 AC: 26AN: 1223182Hom.: 0 Cov.: 30 AF XY: 0.0000130 AC XY: 8AN XY: 614340
GnomAD4 genome AF: 0.0000136 AC: 2AN: 147476Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 1AN XY: 71794
ClinVar
Submissions by phenotype
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Uncertain:2
- -
The c.228-12C>A variant in DARS2 has been reported in 1 individual with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 21493805), and has been identified in 0.007% (6/86090) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs9425753). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1213670) and has been interpreted as a variant of uncertain significance by GeneDx and Invitae. This variant is located in the intron 2 splice region. This region of DARS2 is an established mutational hotspot and most individuals with LBSL have variants in this region (PMID: 24566671). Variants that occur in this intron 2 splice region are known to be leaky, which may explain some variability in disease phenotype (PMID: 24566671). In summary, the clinical significance of the c.228-12C>A variant is uncertain. ACMG/AMP Criteria applied: PM1_supporting, PM2_supporting (Richards 2015). -
not provided Uncertain:2
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21493805) -
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 1213670). This variant has been observed in individual(s) with leukoencephalopathy (PMID: 21493805). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs9425753, gnomAD 0.005%). This sequence change falls in intron 2 of the DARS2 gene. It does not directly change the encoded amino acid sequence of the DARS2 protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at