6-30914638-C-T

Variant summary

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

The ENST00000321897.9(VARS2):c.-199C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,064,428 control chromosomes in the GnomAD database, including 8,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.075 (610 hom., cov: 32)
  • Exomes 𝑓: 0.12 (7814 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.71

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-30914638-C-T is Benign according to our data. Variant chr6-30914638-C-T is described in ClinVar as [Benign]. Clinvar id is 673366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.-27-172C>T		intron_variant		ENST00000676266.1
VARS2	NM_001167733.3	c.-220+294C>T		intron_variant
VARS2	NM_001167734.2	c.59-167C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.-27-172C>T		intron_variant			NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11342 AN: 152122 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.118 AC: 107956 AN: 912188 Hom.: 7814 Cov.: 12 AF XY: 0.117 AC XY: 53085 AN XY: 452834

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0461

Gnomad4 EAS exome AF: 0.00109

Gnomad4 SAS exome AF: 0.0684

Gnomad4 FIN exome AF: 0.0778

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.0747 AC: 11367 AN: 152240 Hom.: 610 Cov.: 32 AF XY: 0.0695 AC XY: 5171 AN XY: 74436

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.0293

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.0699

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0535

Alfa AF: 0.108 Hom.: 685

Bravo AF: 0.0694

Asia WGS AF: 0.0210 AC: 73 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 16, 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	-0.86
Cadd	Benign	0.76
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1264304; hg19: chr6-30882415;