chr1-173831632-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018122.5(DARS2):c.492+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000234 in 1,603,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
DARS2
NM_018122.5 splice_donor, intron
NM_018122.5 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 0.9964
1
1
Clinical Significance
Conservation
PhyloP100: 5.46
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04901961 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-173831632-T-C is Pathogenic according to our data. Variant chr1-173831632-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-173831632-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DARS2 | NM_018122.5 | c.492+2T>C | splice_donor_variant, intron_variant | ENST00000649689.2 | NP_060592.2 | |||
| DARS2 | NM_001365212.1 | c.492+2T>C | splice_donor_variant, intron_variant | NP_001352141.1 | ||||
| DARS2 | NM_001365213.2 | c.492+2T>C | splice_donor_variant, intron_variant | NP_001352142.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DARS2 | ENST00000649689.2 | c.492+2T>C | splice_donor_variant, intron_variant | NM_018122.5 | ENSP00000497569.1 |
Frequencies
GnomAD3 genomes 0.000315 AC: 48AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000331 AC: 83AN: 251028Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135838
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GnomAD4 exome AF: 0.000225 AC: 327AN: 1451196Hom.: 0 Cov.: 28 AF XY: 0.000241 AC XY: 174AN XY: 722742
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GnomAD4 genome 0.000315 AC: 48AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74468
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:9Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The DARS2 c.492+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in at least seven studies, in which it was found in a compound heterozygous state in a total of 22 patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, 17 of whom carried the c.492+2T>C variant in trans with the most common pathogenic DARS2 variant (Scheper et al. 2007; Isohanni et al. 2010; Steenweg et al. 2012; Moore et al. 2012, Martikainen et al. 2013; Alibas et al. 2014; Tylki-Szymanska et al. 2014). Based on in silico analysis, the c.492+2T>C variant is predicted to affect splicing of intron five and cause exon skipping (Scheper et al. 2007; Martikainen et al. 2013). The variant was identified in two out of 575 control subjects in a heterozygous state (Scheper et al. 2007; Isohanni et al. 2010) and is reported at a frequency of 0.00136 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the c.492+2T>C variant is classified as pathogenic for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 15, 2022 | Variant summary: DARS2 c.492+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00033 in 251028 control chromosomes in the gnomAD database, predominantly at a frequency of ~0.002 and ~0.0016 within the Ashkenazi Jewish and Finnish European subpopulations, respectively; however, despite the relatively high frequency, no homozygous occurrences were reported. The carrier frequency of the 492+2T>C variant among Finnish healthy controls was reported to be 1 in 380 in a population-based study (Isohanni_2010), which is mostly consistent with the gnomAD data. On the other hand, the variant c.492+2T>C, has been reported in the literature in several compound heterozygous individuals affected with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement-High Lactate Syndrome (e.g. Scheper_2007, Isohanni_2010, Stellingwerff_2021, Yepez_2022). In addition, some of these studies noted that aberrant splicing was detected with cDNA analysis, resulting in an in-frame deletion of exon 5, which was described as M134_K165del or Lys133_Lys164del at the protein level (Scheper_2007, Yepez_2022). Since no homozygous patients were reported, this suggests that homozygosity for the variant might be embryonic lethal or manifests as a different, yet unidentified phenotype (Isohanni_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | Several individuals share haplotypes involving five or six microsatellite markers on chromosome 1p25. The pathogenic variants 492+2T>C and 455G>T are correlated with two of these haplotypes and are often seen in affected individuals of northeastern European origin. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 24, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Aug 25, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 22, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change affects a donor splice site in intron 5 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 (rs142433332, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (PMID: 17384640). ClinVar contains an entry for this variant (Variation ID: 1062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2023 | 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: 24005482, 20506600, 35379322, 25525159, 17384640, 24558666, 24407472, 29915382, 23065766, 22843165, 34426522, 31589614, 23652419, 19592391, 33977142) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 05, 2022 | PM3, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | DARS2: PVS1, PS4:Moderate - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2022 | The c.492+2T>C intronic alteration consists of a T to C substitution two nucleotides after Intron 5 (C) 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, the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the C allele has an overall frequency of 0.04% (107/282438) total alleles studied. The highest observed frequency was 0.22% (23/10360) of Ashkenazi Jewish alleles. This alteration has been detected in conjunction with other DARS2 alterations in multiple unrelated individuals with mitochondrial aspartyl-tRNA synthetase deficiency (Stellingwerff, 2021; Scheper, 2007). This nucleotide position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is deleterious. The variant is significantly destabilizing to the structure of a necessary domain. 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 pathogenic. - |
Clubfoot;C0018099:Gout;C0020538:Hypertensive disorder;C0311394:Difficulty walking;C0338474:CNS demyelination;C1112256:Sensorimotor neuropathy;C1849134:Impaired vibration sensation in the lower limbs;C4025609:EMG: axonal abnormality;C4551583:Cerebral cortical atrophy;C5399834:Abnormal foot morphology Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Dysmetria;C0751837:Gait ataxia;C1836150:Gait imbalance Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 15, 2015 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
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