chr6-30921099-C-T

Position:

chr6-30921099-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.1514C>T(p.Ser505Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,870 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 52 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 44 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.19

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=0.0051003397).

BP6

Variant 6-30921099-C-T is Benign according to our data. Variant chr6-30921099-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 381460.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 = 0.0129 (1965/152266) while in subpopulation AFR AF= 0.0449 (1866/41524). AF 95% confidence interval is 0.0432. There are 52 homozygotes in gnomad4. There are 859 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VARS2	NM_020442.6 linkuse as main transcript	c.1514C>T	p.Ser505Phe	missense_variant	16/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2 linkuse as main transcript	c.1604C>T	p.Ser535Phe	missense_variant	16/30		NP_001161206.1
VARS2	NM_001167733.3 linkuse as main transcript	c.1094C>T	p.Ser365Phe	missense_variant	15/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 linkuse as main transcript	c.1514C>T	p.Ser505Phe	missense_variant	16/30		NM_020442.6	ENSP00000502585	P3	Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1961

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0450

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00329

AC:

827

AN:

251056

Hom.:

AF XY:

0.00226

AC XY:

307

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.0440

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00125

AC:

1823

AN:

1461604

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

727

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0424

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000863

Gnomad4 OTH exome

AF:

0.00267

GnomAD4 genome

AF:

0.0129

AC:

1965

AN:

152266

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

859

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0449

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00459

Hom.:

Bravo

AF:

0.0147

ESP6500AA

AF:

0.0399

AC:

176

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00395

AC:

480

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0051

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Benign

0.096

Sift

Uncertain

0.0090

D;.;D

Sift4G

Uncertain

0.028

D;D;D

Polyphen

0.91

P;.;.

Vest4

0.34

MVP

0.62

MPC

0.88

ClinPred

0.027

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.49

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

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