6-30915004-G-T

Variant names:

• chr6-30915004-G-T
• rs1264301
• NM_020442.6:c.168G>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.168G>T​(p.Ala56Ala) 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 1,613,132 control chromosomes in the GnomAD database, including 93,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6844 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86715 hom.)
• Consequence: VARS2 NM_020442.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.205

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]

ENSG00000288473 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-30915004-G-T is Benign according to our data. Variant chr6-30915004-G-T is described in ClinVar as [Benign]. Clinvar id is 380150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.205 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 rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.168G>T	p.Ala56Ala	synonymous_variant	Exon 2 of 30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.258G>T	p.Ala86Ala	synonymous_variant	Exon 2 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.-219-152G>T		intron_variant	Intron 1 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.168G>T	p.Ala56Ala	synonymous_variant	Exon 2 of 30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42566 AN: 151960 Hom.: 6847 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.317 AC: 78291 AN: 247178 Hom.: 13257 AF XY: 0.324 AC XY: 43563 AN XY: 134538

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.339 AC: 495848 AN: 1461056 Hom.: 86715 Cov.: 53 AF XY: 0.339 AC XY: 246547 AN XY: 726846

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: 42576 AN: 152076 Hom.: 6844 Cov.: 32 AF XY: 0.281 AC XY: 20879 AN XY: 74310

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.279

Alfa AF: 0.343 Hom.: 11889

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 725 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 16, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% 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: 47. Only high quality variants are reported. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.6
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1264301; hg19: chr6-30882781; COSMIC: COSV52558864; COSMIC: COSV52558864;