rs6926723

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020442.6(VARS2):c.190G>A(p.Gly64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,613,386 control chromosomes in the GnomAD database, including 2,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 506 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1507 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.714

Publications

23 publications found

Variant links:

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)

VARS2 links:

ENSG00000288473 (HGNC:):

ENSG00000288473 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015696287).

BP6

Variant 6-30915026-G-A is Benign according to our data. Variant chr6-30915026-G-A is described in ClinVar as Benign. ClinVar VariationId is 380189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6 link	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 30	ENST00000676266.1	NP_065175.4	Q5ST30-1B4E0K6B4DG77
VARS2	NM_001167734.2 link	c.280G>A	p.Gly94Arg	missense_variant	Exon 2 of 30		NP_001161206.1	Q5ST30-4A0A1U9X9B3
VARS2	NM_001167733.3 link	c.-219-130G>A		intron_variant	Intron 1 of 28		NP_001161205.1	Q5ST30-3B4E0K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 link	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 30		NM_020442.6	ENSP00000502585.1		Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.0646

AC:

9829

AN:

152124

Hom.:

504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0891

Gnomad ASJ

AF:

0.0913

Gnomad EAS

AF:

0.0631

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0319

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0506

AC:

12562

AN:

248130

AF XY:

0.0467

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0992

Gnomad ASJ exome

AF:

0.0930

Gnomad EAS exome

AF:

0.0627

Gnomad FIN exome

AF:

0.00925

Gnomad NFE exome

AF:

0.0325

Gnomad OTH exome

AF:

0.0497

GnomAD4 exome

AF:

0.0365

AC:

53278

AN:

1461144

Hom.:

1507

Cov.:

AF XY:

0.0362

AC XY:

26295

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.133

AC:

4443

AN:

33380

American (AMR)

AF:

0.0966

AC:

4313

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0895

AC:

2340

AN:

26132

East Asian (EAS)

AF:

0.0616

AC:

2447

AN:

39700

South Asian (SAS)

AF:

0.0335

AC:

2885

AN:

86224

European-Finnish (FIN)

AF:

0.00981

AC:

520

AN:

53012

Middle Eastern (MID)

AF:

0.0596

AC:

344

AN:

5768

European-Non Finnish (NFE)

AF:

0.0297

AC:

33027

AN:

1111918

Other (OTH)

AF:

0.0490

AC:

2959

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2874

5748

8622

11496

14370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1360

2720

4080

5440

6800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0646

AC:

9842

AN:

152242

Hom.:

506

Cov.:

AF XY:

0.0638

AC XY:

4751

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.126

AC:

5245

AN:

41542

American (AMR)

AF:

0.0891

AC:

1363

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0913

AC:

317

AN:

3472

East Asian (EAS)

AF:

0.0632

AC:

327

AN:

5172

South Asian (SAS)

AF:

0.0317

AC:

153

AN:

4828

European-Finnish (FIN)

AF:

0.0107

AC:

114

AN:

10608

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0319

AC:

2168

AN:

68012

Other (OTH)

AF:

0.0649

AC:

137

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

457

913

1370

1826

2283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0444

Hom.:

804

Bravo

AF:

0.0748

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.117

AC:

354

ESP6500EA

AF:

0.0353

AC:

191

ExAC

AF:

0.0484

AC:

5866

Asia WGS

AF:

0.0560

AC:

194

AN:

3478

EpiCase

AF:

0.0366

EpiControl

AF:

0.0371

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.62

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0034

T;T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.31

T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

-0.71

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.010

Sift

Benign

0.45

T;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.026

MutPred

0.12

Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);.;Gain of MoRF binding (P = 0.0157);

MPC

0.54

ClinPred

0.0061

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.18

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over