6-30916659-A-G

Position:

• chr6-30916659-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020442.6(VARS2):​c.672-219A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 587,934 control chromosomes in the GnomAD database, including 32,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6828 hom., cov: 31)
  • Exomes 𝑓: 0.33 (25257 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.215

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]

VARS2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-30916659-A-G is Benign according to our data. Variant chr6-30916659-A-G is described in ClinVar as [Benign]. Clinvar id is 669590.Status of the report is criteria_provided_single_submitter, 1 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	Protein	UniProt
VARS2	NM_020442.6	c.672-219A>G		intron_variant		ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.762-219A>G		intron_variant			NP_001161206.1
VARS2	NM_001167733.3	c.252-219A>G		intron_variant			NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.672-219A>G		intron_variant			NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42481 AN: 151666 Hom.: 6831 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.254

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

GnomAD4 exome AF: 0.332 AC: 144653 AN: 436150 Hom.: 25257 Cov.: 4 AF XY: 0.330 AC XY: 75556 AN XY: 228954

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.373

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.280 AC: 42491 AN: 151784 Hom.: 6828 Cov.: 31 AF XY: 0.281 AC XY: 20830 AN XY: 74164

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.402

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: 0.331 Hom.: 5635

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 725 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.96
CADD	Benign	2.3
DANN	Benign	0.47

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: rs1264298; hg19: chr6-30884436;