6-30915004-G-T

Variant names:

• chr6-30915004-G-T
• rs1264301
• NM_020442.6:c.168G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000288473 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020442.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.168G>T	p.Ala56Ala	synonymous	Exon 2 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.258G>T	p.Ala86Ala	synonymous	Exon 2 of 30	NP_001161206.1
	VARS2	NM_001167733.3		c.-219-152G>T		intron	N/A	NP_001161205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.168G>T	p.Ala56Ala	synonymous	Exon 2 of 30	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 29	ENSP00000316092.5
	VARS2	ENST00000541562.6	TSL:2	c.168G>T	p.Ala56Ala	synonymous	Exon 2 of 30	ENSP00000441000.2

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

GnomAD2 exomes AF: 0.317 AC: 78291 AN: 247178 AF XY: 0.324

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 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

African (AFR) AF: 0.116 AC: 3866 AN: 33438

American (AMR) AF: 0.220 AC: 9841 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9794 AN: 26134

East Asian (EAS) AF: 0.241 AC: 9553 AN: 39700

South Asian (SAS) AF: 0.276 AC: 23792 AN: 86238

European-Finnish (FIN) AF: 0.386 AC: 20359 AN: 52776

Middle Eastern (MID) AF: 0.330 AC: 1901 AN: 5768

European-Non Finnish (NFE) AF: 0.358 AC: 397942 AN: 1111926

Other (OTH) AF: 0.311 AC: 18800 AN: 60386

GnomAD4 genome AF: 0.280 AC: 42576 AN: 152076 Hom.: 6844 Cov.: 32 AF XY: 0.281 AC XY: 20879 AN XY: 74310

African (AFR) AF: 0.125 AC: 5169 AN: 41486

American (AMR) AF: 0.242 AC: 3708 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1306 AN: 5162

South Asian (SAS) AF: 0.262 AC: 1262 AN: 4812

European-Finnish (FIN) AF: 0.393 AC: 4146 AN: 10556

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24613 AN: 67984

Other (OTH) AF: 0.279 AC: 589 AN: 2112

Alfa AF: 0.331 Hom.: 26317

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.6
DANN	Benign	0.74
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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