6-30924387-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020442.6(VARS2):c.2500C>T(p.Arg834Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,612,612 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R834H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 7 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.132

Publications

1 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=0.0027604997).

BP6

Variant 6-30924387-C-T is Benign according to our data. Variant chr6-30924387-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00453 (690/152380) while in subpopulation AFR AF = 0.0136 (564/41596). AF 95% confidence interval is 0.0126. There are 3 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6 link	c.2500C>T	p.Arg834Cys	missense_variant	Exon 26 of 30	ENST00000676266.1	NP_065175.4	Q5ST30-1B4E0K6B4DG77
VARS2	NM_001167734.2 link	c.2590C>T	p.Arg864Cys	missense_variant	Exon 26 of 30		NP_001161206.1	Q5ST30-4A0A1U9X9B3
VARS2	NM_001167733.3 link	c.2080C>T	p.Arg694Cys	missense_variant	Exon 25 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.2500C>T	p.Arg834Cys	missense_variant	Exon 26 of 30		NM_020442.6	ENSP00000502585.1		Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

687

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00108

AC:

262

AN:

243656

AF XY:

0.000803

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000554

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000485

AC:

708

AN:

1460232

Hom.:

Cov.:

AF XY:

0.000427

AC XY:

310

AN XY:

726416

show subpopulations

African (AFR)

AF:

0.0149

AC:

500

AN:

33460

American (AMR)

AF:

0.00212

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111976

Other (OTH)

AF:

0.00126

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00453

AC:

690

AN:

152380

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0136

AC:

564

AN:

41596

American (AMR)

AF:

0.00712

AC:

109

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00231

Hom.:

Bravo

AF:

0.00670

ESP6500AA

AF:

0.0153

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00120

AC:

141

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

VARS2-related disorder

Benign:1

Jun 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.1

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0039

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.32

N;.;.

PhyloP100

-0.13

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.024

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.057

B;.;.

Vest4

0.11

MVP

0.055

MPC

0.61

ClinPred

0.0027

GERP RS

-0.59

Varity_R

0.12

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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