rs2532938

Positions:

• chr6-30926054-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020442.6(VARS2):​c.3090+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,612,636 control chromosomes in the GnomAD database, including 93,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6836 hom., cov: 33)
  • Exomes 𝑓: 0.34 (86675 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.54

Genes affected

VARS2 (HGNC:21642): (valyl-tRNA synthetase 2, mitochondrial) This gene encodes a mitochondrial aminoacyl-tRNA synthetase, which catalyzes the attachment of valine to tRNA(Val) for mitochondrial translation. Mutations in this gene cause combined oxidative phosphorylation deficiency-20, and are also associated with early-onset mitochondrial encephalopathies. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-30926054-G-A is Benign according to our data. Variant chr6-30926054-G-A is described in ClinVar as [Benign]. Clinvar id is 1292282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.3090+46G>A		intron_variant		ENST00000676266.1
VARS2	NM_001167733.3	c.2670+46G>A		intron_variant
VARS2	NM_001167734.2	c.3180+46G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.3090+46G>A		intron_variant			NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42555 AN: 152038 Hom.: 6839 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.316 AC: 77861 AN: 246172 Hom.: 13166 AF XY: 0.324 AC XY: 43475 AN XY: 134224

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.339 AC: 495623 AN: 1460480 Hom.: 86675 Cov.: 63 AF XY: 0.339 AC XY: 246421 AN XY: 726516

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.280 AC: 42565 AN: 152156 Hom.: 6836 Cov.: 33 AF XY: 0.281 AC XY: 20883 AN XY: 74378

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.279

Alfa AF: 0.345 Hom.: 6272

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 725 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 47. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.059
DANN	Benign	0.54

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: rs2532938; hg19: chr6-30893831; COSMIC: COSV58915042; COSMIC: COSV58915042;