1-173828321-C-G

Variant names:

• chr1-173828321-C-G
• rs9425753
• NM_018122.5:c.228-12C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018122.5(DARS2):​c.228-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,370,752 control chromosomes in the GnomAD database, including 3,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1478 hom., cov: 30)
  • Exomes 𝑓: 0.011 (1524 hom.)
• Consequence: DARS2 NM_018122.5 intron
• Scores: Splicing: ADA: 0.001504
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.138
• Publications: 4 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-173828321-C-G is Benign according to our data. Variant chr1-173828321-C-G is described in ClinVar as Benign. ClinVar VariationId is 137070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	NM_018122.5	MANE Select	c.228-12C>G		intron	N/A	NP_060592.2
	DARS2	NM_001365212.1		c.228-12C>G		intron	N/A	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.228-12C>G		intron	N/A	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.228-12C>G		intron	N/A	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.228-12C>G		intron	N/A	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.228-12C>G		intron	N/A	ENSP00000563415.1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11595 AN: 147460 Hom.: 1474 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.00160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.0629

GnomAD2 exomes AF: 0.0219 AC: 5479 AN: 250472 AF XY: 0.0165

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0108 AC: 13234 AN: 1223162 Hom.: 1524 Cov.: 30 AF XY: 0.00958 AC XY: 5888 AN XY: 614336

African (AFR) AF: 0.305 AC: 9179 AN: 30090

American (AMR) AF: 0.0172 AC: 718 AN: 41816

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 608 AN: 20288

East Asian (EAS) AF: 0.000631 AC: 19 AN: 30118

South Asian (SAS) AF: 0.00105 AC: 86 AN: 81728

European-Finnish (FIN) AF: 0.0000219 AC: 1 AN: 45708

Middle Eastern (MID) AF: 0.0295 AC: 143 AN: 4852

European-Non Finnish (NFE) AF: 0.00132 AC: 1212 AN: 919410

Other (OTH) AF: 0.0258 AC: 1268 AN: 49152

GnomAD4 genome AF: 0.0788 AC: 11632 AN: 147590 Hom.: 1478 Cov.: 30 AF XY: 0.0768 AC XY: 5522 AN XY: 71922

African (AFR) AF: 0.266 AC: 10799 AN: 40654

American (AMR) AF: 0.0349 AC: 513 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 87 AN: 3396

East Asian (EAS) AF: 0.000212 AC: 1 AN: 4728

South Asian (SAS) AF: 0.00114 AC: 5 AN: 4374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9792

Middle Eastern (MID) AF: 0.0144 AC: 4 AN: 278

European-Non Finnish (NFE) AF: 0.00144 AC: 96 AN: 66714

Other (OTH) AF: 0.0623 AC: 127 AN: 2040

Alfa AF: 0.00793 Hom.: 15

Bravo AF: 0.0878

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.63
DANN	Benign	0.73
PhyloP100		-0.14
Mutation Taster		=27/73	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.050		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: rs9425753; hg19: chr1-173797459;