rs2068871

Variant names:

• chr1-173827031-A-G
• rs2068871
• NM_018122.5:c.227+245A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018122.5(DARS2):​c.227+245A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 152,260 control chromosomes in the GnomAD database, including 739 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.082 (739 hom., cov: 32)
• Consequence: DARS2 NM_018122.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-173827031-A-G is Benign according to our data. Variant chr1-173827031-A-G is described in ClinVar as Benign. ClinVar VariationId is 683695.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.227+245A>G		intron_variant	Intron 2 of 16	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.227+245A>G		intron_variant	Intron 2 of 15		NP_001352141.1
DARS2	NM_001365213.2	c.227+245A>G		intron_variant	Intron 2 of 13		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.227+245A>G		intron_variant	Intron 2 of 16		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes AF: 0.0824 AC: 12537 AN: 152142 Hom.: 740 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0888

Gnomad OTH AF: 0.0899

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0823 AC: 12538 AN: 152260 Hom.: 739 Cov.: 32 AF XY: 0.0829 AC XY: 6172 AN XY: 74450

African (AFR) AF: 0.0394 AC: 1637 AN: 41556

American (AMR) AF: 0.0752 AC: 1150 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1637 AN: 5166

South Asian (SAS) AF: 0.100 AC: 485 AN: 4828

European-Finnish (FIN) AF: 0.0794 AC: 843 AN: 10616

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0888 AC: 6041 AN: 68012

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.0878 Hom.: 3042

Bravo AF: 0.0803

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.055
DANN	Benign	0.77
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2068871; hg19: chr1-173796169;