GeneBe

NM_018122.5:c.-219C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018122.5(DARS2):​c.-219C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 497,832 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

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

DARS2
NM_018122.5 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.271

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]
CENPL (HGNC:17879): (centromere protein L) CENPL is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006) [PubMed 16622420].[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS2NM_018122.5 linkc.-219C>T 5_prime_UTR_variant Exon 1 of 17 ENST00000649689.2 NP_060592.2 Q6PI48Q9H9J7
CENPLNM_001387287.1 linkc.-901G>A upstream_gene_variant ENST00000682279.1 NP_001374216.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DARS2ENST00000649689.2 linkc.-219C>T 5_prime_UTR_variant Exon 1 of 17 NM_018122.5 ENSP00000497569.1 Q6PI48
CENPLENST00000682279.1 linkc.-901G>A upstream_gene_variant NM_001387287.1 ENSP00000507473.1 Q8N0S6-1

Frequencies

GnomAD3 genomes
AF:
0.000559
AC:
85
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000660
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00104
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000538
AC:
186
AN:
345620
Hom.:
0
Cov.:
5
AF XY:
0.000453
AC XY:
85
AN XY:
187442
show subpopulations
African (AFR)
AF:
0.000431
AC:
4
AN:
9286
American (AMR)
AF:
0.00
AC:
0
AN:
17262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
9484
East Asian (EAS)
AF:
0.00
AC:
0
AN:
17900
South Asian (SAS)
AF:
0.00
AC:
0
AN:
47648
European-Finnish (FIN)
AF:
0.000396
AC:
6
AN:
15170
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1344
European-Non Finnish (NFE)
AF:
0.000802
AC:
168
AN:
209516
Other (OTH)
AF:
0.000444
AC:
8
AN:
18010
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
8
16
25
33
41
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.000558
AC:
85
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.000524
AC XY:
39
AN XY:
74422
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41524
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.000660
AC:
7
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00104
AC:
71
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.534
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00101
Hom.:
0
Bravo
AF:
0.000476

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
7.2
DANN
Benign
0.87
PhyloP100
-0.27
PromoterAI
0.015
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs569117944; hg19: chr1-173794149; API