rs4678

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3146G>A(p.Arg1049Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,612,978 control chromosomes in the GnomAD database, including 29,832 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1049L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 1916 hom., cov: 33)

Exomes 𝑓: 0.19 ( 27916 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.972

Publications

65 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=0.0012257993).

BP6

Variant 6-30926164-G-A is Benign according to our data. Variant chr6-30926164-G-A is described in ClinVar as Benign. ClinVar VariationId is 380164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VARS2	NM_020442.6	MANE Select	c.3146G>A	p.Arg1049Gln	missense	Exon 30 of 30	NP_065175.4
VARS2	NM_001167734.2		c.3236G>A	p.Arg1079Gln	missense	Exon 30 of 30	NP_001161206.1	A0A1U9X9B3
VARS2	NM_001167733.3		c.2726G>A	p.Arg909Gln	missense	Exon 29 of 29	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VARS2	ENST00000676266.1	MANE Select	c.3146G>A	p.Arg1049Gln	missense	Exon 30 of 30	ENSP00000502585.1	Q5ST30-1
VARS2	ENST00000321897.9	TSL:1	c.3146G>A	p.Arg1049Gln	missense	Exon 29 of 29	ENSP00000316092.5	Q5ST30-1
VARS2	ENST00000476162.5	TSL:1	n.1933G>A		non_coding_transcript_exon	Exon 18 of 18

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22729

AN:

152104

Hom.:

1912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.0756

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.0341

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.144

AC:

35496

AN:

246544

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0624

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.0342

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.195

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.188

AC:

274406

AN:

1460756

Hom.:

27916

Cov.:

AF XY:

0.187

AC XY:

135802

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.122

AC:

4070

AN:

33480

American (AMR)

AF:

0.0647

AC:

2894

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

4076

AN:

26136

East Asian (EAS)

AF:

0.0229

AC:

908

AN:

39700

South Asian (SAS)

AF:

0.128

AC:

11025

AN:

86258

European-Finnish (FIN)

AF:

0.133

AC:

6957

AN:

52312

Middle Eastern (MID)

AF:

0.111

AC:

642

AN:

5768

European-Non Finnish (NFE)

AF:

0.210

AC:

233540

AN:

1111994

Other (OTH)

AF:

0.170

AC:

10294

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13804

27608

41413

55217

69021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7972

15944

23916

31888

39860

<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:

0.150

AC:

22764

AN:

152222

Hom.:

1916

Cov.:

AF XY:

0.143

AC XY:

10640

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.119

AC:

4955

AN:

41540

American (AMR)

AF:

0.0753

AC:

1152

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

495

AN:

3470

East Asian (EAS)

AF:

0.0341

AC:

177

AN:

5186

South Asian (SAS)

AF:

0.109

AC:

527

AN:

4818

European-Finnish (FIN)

AF:

0.136

AC:

1441

AN:

10598

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.199

AC:

13517

AN:

68000

Other (OTH)

AF:

0.125

AC:

265

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

999

1999

2998

3998

4997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.184

Hom.:

12536

Bravo

AF:

0.145

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.217

AC:

836

ESP6500AA

AF:

0.122

AC:

367

ESP6500EA

AF:

0.193

AC:

1047

ExAC

AF:

0.145

AC:

17106

Asia WGS

AF:

0.0810

AC:

282

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.187

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.38

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.00072

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

PhyloP100

-0.97

PrimateAI

Benign

0.23

PROVEAN

Benign

0.43

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.037

MPC

0.52

ClinPred

0.00030

GERP RS

-8.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.045

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over