rs2517467

Positions:

• chr6-30921483-G-A
• chr6-30921483-G-C

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.1633-106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,442,894 control chromosomes in the GnomAD database, including 218,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21794 hom., cov: 32)
  • Exomes 𝑓: 0.54 (196247 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.764

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=-0.89).
• BP6: Variant 6-30921483-G-A is Benign according to our data. Variant chr6-30921483-G-A is described in ClinVar as [Benign]. Clinvar id is 1264235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.1633-106G>A		intron_variant		ENST00000676266.1
VARS2	NM_001167733.3	c.1213-106G>A		intron_variant
VARS2	NM_001167734.2	c.1723-106G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.1633-106G>A		intron_variant			NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79239 AN: 151908 Hom.: 21779 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.544 AC: 701678 AN: 1290868 Hom.: 196247 Cov.: 20 AF XY: 0.550 AC XY: 353011 AN XY: 642332

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.803

Gnomad4 SAS exome AF: 0.730

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.555

GnomAD4 genome AF: 0.522 AC: 79289 AN: 152026 Hom.: 21794 Cov.: 32 AF XY: 0.534 AC XY: 39670 AN XY: 74328

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.602

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.843

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.521

Alfa AF: 0.531 Hom.: 15354

Bravo AF: 0.508

Asia WGS AF: 0.749 AC: 2607 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 81% 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: 75. 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	-0.89
CADD	Benign	1.8
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2517467; hg19: chr6-30889260;