6-30924387-C-T

Position:

chr6-30924387-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:3

Conservation

PhyloP100: -0.132

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VARS2	NM_020442.6 linkuse as main transcript	c.2500C>T	p.Arg834Cys	missense_variant	26/30	ENST00000676266.1
VARS2	NM_001167734.2 linkuse as main transcript	c.2590C>T	p.Arg864Cys	missense_variant	26/30
VARS2	NM_001167733.3 linkuse as main transcript	c.2080C>T	p.Arg694Cys	missense_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1 linkuse as main transcript	c.2500C>T	p.Arg834Cys	missense_variant	26/30		NM_020442.6	P3	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

GnomAD3 exomes

AF:

0.00108

AC:

262

AN:

243656

Hom.:

AF XY:

0.000803

AC XY:

107

AN XY:

133310

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 SAS exome

AF:

0.0000329

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

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.00212

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00453

AC:

690

AN:

152380

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00214

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -

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

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;.;.

MutationTaster

Benign

1.0

N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over