rs2074511

Positions:

• chr6-30921612-T-C

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.1656T>C​(p.Val552Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,606,782 control chromosomes in the GnomAD database, including 39,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4000 hom., cov: 32)
  • Exomes 𝑓: 0.19 (35175 hom.)
• Consequence: VARS2 NM_020442.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.45

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-30921612-T-C is Benign according to our data. Variant chr6-30921612-T-C is described in ClinVar as [Benign]. Clinvar id is 380156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.1656T>C	p.Val552Val	synonymous_variant	18/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.1746T>C	p.Val582Val	synonymous_variant	18/30		NP_001161206.1
VARS2	NM_001167733.3	c.1236T>C	p.Val412Val	synonymous_variant	17/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.1656T>C	p.Val552Val	synonymous_variant	18/30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30869 AN: 151860 Hom.: 3988 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.269 AC: 63022 AN: 233960 Hom.: 10934 AF XY: 0.267 AC XY: 33920 AN XY: 127076

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.546

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.195 AC: 283500 AN: 1454804 Hom.: 35175 Cov.: 36 AF XY: 0.200 AC XY: 144322 AN XY: 723014

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.555

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.203 AC: 30902 AN: 151978 Hom.: 4000 Cov.: 32 AF XY: 0.214 AC XY: 15889 AN XY: 74250

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.574

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.201

Alfa AF: 0.178 Hom.: 3704

Bravo AF: 0.203

Asia WGS AF: 0.501 AC: 1740 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 55% 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: 51. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.19
DANN	Benign	0.73
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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: rs2074511; hg19: chr6-30889389; COSMIC: COSV58911919; COSMIC: COSV58911919;