rs1264302

chr6-30914857-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020442.6(VARS2):c.21C>T(p.Ala7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,612,758 control chromosomes in the GnomAD database, including 93,516 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: 32)
  • Exomes 𝑓: 0.34 (86688 hom.)
• Consequence: VARS2 NM_020442.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.184

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-30914857-C-T is Benign according to our data. Variant chr6-30914857-C-T is described in ClinVar as [Benign]. Clinvar id is 380149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• 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.21C>T	p.Ala7=	synonymous_variant	2/30	ENST00000676266.1
VARS2	NM_001167734.2	c.111C>T	p.Ala37=	synonymous_variant	2/30
VARS2	NM_001167733.3	c.-219-299C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.21C>T	p.Ala7=	synonymous_variant	2/30		NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42528 AN: 151942 Hom.: 6831 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.316 AC: 77929 AN: 246428 Hom.: 13178 AF XY: 0.324 AC XY: 43513 AN XY: 134366

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: 0.274

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.339 AC: 495673 AN: 1460696 Hom.: 86688 Cov.: 60 AF XY: 0.339 AC XY: 246474 AN XY: 726678

Gnomad4 AFR exome AF: 0.116

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: 42538 AN: 152062 Hom.: 6828 Cov.: 32 AF XY: 0.281 AC XY: 20858 AN XY: 74316

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.280

Alfa AF: 0.346 Hom.: 12105

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 724 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2015

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	-0.63
Cadd	Benign	9.3
Dann	Benign	0.90

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: rs1264302; hg19: chr6-30882634; COSMIC: COSV52558947; COSMIC: COSV52558947;