rs367543010

chr1-173828312-T-TCchr1-173828312-T-TCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018122.5(DARS2):c.228-21_228-20insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,547,144 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (24 hom., cov: 27)
  • Exomes 𝑓: 0.0033 (28 hom.)
• Consequence: DARS2 NM_018122.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-173828312-T-TC is Benign according to our data. Variant chr1-173828312-T-TC is described in ClinVar as [Likely_benign]. Clinvar id is 559195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS2	NM_018122.5	c.228-21_228-20insC		intron_variant		ENST00000649689.2
DARS2	NM_001365212.1	c.228-21_228-20insC		intron_variant
DARS2	NM_001365213.2	c.228-21_228-20insC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS2	ENST00000649689.2	c.228-21_228-20insC		intron_variant			NM_018122.5	P1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 992 AN: 149298 Hom.: 24 Cov.: 27

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000905

Gnomad OTH AF: 0.00341

GnomAD4 exome AF: 0.00329 AC: 4593 AN: 1397728 Hom.: 28 Cov.: 22 AF XY: 0.00422 AC XY: 2939 AN XY: 695708

Gnomad4 AFR exome AF: 0.00500

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00454

Gnomad4 EAS exome AF: 0.00737

Gnomad4 SAS exome AF: 0.0331

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.000970

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00667 AC: 996 AN: 149416 Hom.: 24 Cov.: 27 AF XY: 0.00787 AC XY: 574 AN XY: 72968

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00221

Gnomad4 ASJ AF: 0.0108

Gnomad4 EAS AF: 0.0167

Gnomad4 SAS AF: 0.0625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000905

Gnomad4 OTH AF: 0.00338

Alfa AF: 0.00359 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	This variant is associated with the following publications: (PMID: 31664448) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	DARS2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs367543010; hg19: chr1-173797450;