6-30922706-G-T

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.2038G>T(p.Val680Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.334 in 1,611,656 control chromosomes in the GnomAD database, including 93,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6844 hom., cov: 33)

Exomes 𝑓: 0.34 ( 86665 hom. )

Consequence

VARS2
NM_020442.6 missense, splice_region

Scores

Splicing: ADA: 0.9522

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.29

Publications

46 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=0.0024447143).

BP6

Variant 6-30922706-G-T is Benign according to our data. Variant chr6-30922706-G-T is described in ClinVar as Benign. ClinVar VariationId is 380157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 link	c.2038G>T	p.Val680Leu	missense_variant, splice_region_variant	Exon 22 of 30	ENST00000676266.1	NP_065175.4	Q5ST30-1B4E0K6B4DG77
VARS2	NM_001167734.2 link	c.2128G>T	p.Val710Leu	missense_variant, splice_region_variant	Exon 22 of 30		NP_001161206.1	Q5ST30-4A0A1U9X9B3
VARS2	NM_001167733.3 link	c.1618G>T	p.Val540Leu	missense_variant, splice_region_variant	Exon 21 of 29		NP_001161205.1	Q5ST30-3B4E0K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 link	c.2038G>T	p.Val680Leu	missense_variant, splice_region_variant	Exon 22 of 30		NM_020442.6	ENSP00000502585.1		Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.280

AC:

42592

AN:

152058

Hom.:

6847

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.402

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.393

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.280

GnomAD2 exomes

AF:

0.316

AC:

77549

AN:

245306

AF XY:

0.324

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.392

Gnomad NFE exome

AF:

0.369

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.339

AC:

495350

AN:

1459482

Hom.:

86665

Cov.:

AF XY:

0.339

AC XY:

246296

AN XY:

726010

show subpopulations

African (AFR)

AF:

0.115

AC:

3864

AN:

33464

American (AMR)

AF:

0.220

AC:

9807

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9759

AN:

26050

East Asian (EAS)

AF:

0.241

AC:

9551

AN:

39688

South Asian (SAS)

AF:

0.276

AC:

23762

AN:

86080

European-Finnish (FIN)

AF:

0.386

AC:

20169

AN:

52284

Middle Eastern (MID)

AF:

0.330

AC:

1898

AN:

5756

European-Non Finnish (NFE)

AF:

0.358

AC:

397736

AN:

1111250

Other (OTH)

AF:

0.312

AC:

18804

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17389

34778

52168

69557

86946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12420

24840

37260

49680

62100

<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:

0.280

AC:

42601

AN:

152174

Hom.:

6844

Cov.:

AF XY:

0.281

AC XY:

20908

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.125

AC:

5177

AN:

41550

American (AMR)

AF:

0.242

AC:

3706

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

1393

AN:

3468

East Asian (EAS)

AF:

0.254

AC:

1314

AN:

5182

South Asian (SAS)

AF:

0.263

AC:

1270

AN:

4822

European-Finnish (FIN)

AF:

0.393

AC:

4152

AN:

10576

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.362

AC:

24615

AN:

67970

Other (OTH)

AF:

0.277

AC:

584

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1549

3098

4647

6196

7745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.338

Hom.:

40170

Bravo

AF:

0.263

TwinsUK

AF:

0.355

AC:

1317

ALSPAC

AF:

0.368

AC:

1419

ESP6500AA

AF:

0.146

AC:

440

ESP6500EA

AF:

0.377

AC:

2039

ExAC

AF:

0.319

AC:

37430

Asia WGS

AF:

0.207

AC:

725

AN:

3476

EpiCase

AF:

0.369

EpiControl

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

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. -

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

- -

Combined oxidative phosphorylation defect type 20

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0035

T;.;.

Eigen

Benign

0.029

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.27

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

L;.;.

PhyloP100

4.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.034

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.070

MutPred

0.15

Gain of catalytic residue at V680 (P = 0.0579);.;.;

MPC

0.50

ClinPred

0.0041

GERP RS

5.3

Varity_R

0.20

gMVP

0.27

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.85

Splicevardb

2.0

SpliceAI score (max)

0.020

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