Genetic Variant VARS2:c.-376C>T (chr6-30914461-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001167734.2(VARS2):c.50C>T(p.Pro17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VARS2
NM_001167734.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.513

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07506174).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167734.2. 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.-28+117C>T		intron	N/A	NP_065175.4
VARS2	NM_001167734.2		c.50C>T	p.Pro17Leu	missense	Exon 1 of 30	NP_001161206.1	A0A1U9X9B3
VARS2	NM_001167733.3		c.-220+117C>T		intron	N/A	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VARS2	ENST00000321897.9	TSL:1	c.-376C>T	5_prime_UTR	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
VARS2	ENST00000676266.1	MANE Select	c.-28+117C>T	intron	N/A	ENSP00000502585.1	Q5ST30-1
VARS2	ENST00000541562.6	TSL:2	c.-41C>T	5_prime_UTR	Exon 1 of 30	ENSP00000441000.2	Q5ST30-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1161810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

555730

African (AFR)

AF:

0.00

AC:

AN:

23744

American (AMR)

AF:

0.00

AC:

AN:

11270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15886

East Asian (EAS)

AF:

0.00

AC:

AN:

28074

South Asian (SAS)

AF:

0.00

AC:

AN:

37506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4824

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

967182

Other (OTH)

AF:

0.00

AC:

AN:

47668

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.8

(source)

DANN

Benign

0.81

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.54

M_CAP

Benign

0.0093

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.91

PhyloP100

-0.51

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.30

REVEL

Benign

0.075

Sift

Benign

0.094

Sift4G

Pathogenic

0.0

Vest4

0.082

MutPred

0.37

Loss of disorder (P = 0.0252)

MVP

0.15

MPC

0.45

ClinPred

0.24

GERP RS

0.27

PromoterAI

0.076

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over