Genetic Variant VARS2:p.Val680Met (chr6-30922706-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020442.6(VARS2):c.2038G>A(p.Val680Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V680L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VARS2
NM_020442.6 missense, splice_region

Scores

Splicing: ADA: 0.9969

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.29

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.384305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6 link	c.2038G>A	p.Val680Met	missense_variant, splice_region_variant	Exon 22 of 30	ENST00000676266.1	NP_065175.4	Q5ST30-1B4E0K6B4DG77
VARS2	NM_001167734.2 link	c.2128G>A	p.Val710Met	missense_variant, splice_region_variant	Exon 22 of 30		NP_001161206.1	Q5ST30-4A0A1U9X9B3
VARS2	NM_001167733.3 link	c.1618G>A	p.Val540Met	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>A	p.Val680Met	missense_variant, splice_region_variant	Exon 22 of 30		NM_020442.6	ENSP00000502585.1		Q5ST30-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459802

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111472

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0032

T;.;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

4.3

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.32

N;.;N

REVEL

Benign

0.061

Sift

Benign

0.036

D;.;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.079

B;.;.

Vest4

0.087

MutPred

0.30

Gain of disorder (P = 0.0438);.;.;

MVP

0.55

MPC

0.55

ClinPred

0.60

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.21

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over