6-30914857-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020442.6(VARS2):c.21C>T(p.Ala7Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,612,758 control chromosomes in the GnomAD database, including 93,516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6828 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86688 hom. )

Consequence

VARS2
NM_020442.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.184

Publications

32 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 6-30914857-C-T is Benign according to our data. Variant chr6-30914857-C-T is described in ClinVar as [Benign]. Clinvar id is 380149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.184 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6 link	c.21C>T	p.Ala7Ala	synonymous_variant	Exon 2 of 30	ENST00000676266.1	NP_065175.4	Q5ST30-1B4E0K6B4DG77
VARS2	NM_001167734.2 link	c.111C>T	p.Ala37Ala	synonymous_variant	Exon 2 of 30		NP_001161206.1	Q5ST30-4A0A1U9X9B3
VARS2	NM_001167733.3 link	c.-219-299C>T		intron_variant	Intron 1 of 28		NP_001161205.1	Q5ST30-3B4E0K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 link	c.21C>T	p.Ala7Ala	synonymous_variant	Exon 2 of 30		NM_020442.6	ENSP00000502585.1		Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.280

AC:

42528

AN:

151942

Hom.:

6831

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.379

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.283

GnomAD2 exomes

AF:

0.316

AC:

77929

AN:

246428

AF XY:

0.324

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.283

Gnomad FIN exome

AF:

0.392

Gnomad NFE exome

AF:

0.369

Gnomad OTH exome

AF:

0.334

GnomAD4 exome

AF:

0.339

AC:

495673

AN:

1460696

Hom.:

86688

Cov.:

AF XY:

0.339

AC XY:

246474

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.116

AC:

3867

AN:

33480

American (AMR)

AF:

0.220

AC:

9839

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9794

AN:

26136

East Asian (EAS)

AF:

0.241

AC:

9552

AN:

39698

South Asian (SAS)

AF:

0.276

AC:

23791

AN:

86254

European-Finnish (FIN)

AF:

0.386

AC:

20172

AN:

52294

Middle Eastern (MID)

AF:

0.330

AC:

1901

AN:

5768

European-Non Finnish (NFE)

AF:

0.358

AC:

397958

AN:

1111962

Other (OTH)

AF:

0.311

AC:

18799

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

19467

38933

58400

77866

97333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12422

24844

37266

49688

62110

<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:

0.280

AC:

42538

AN:

152062

Hom.:

6828

Cov.:

AF XY:

0.281

AC XY:

20858

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.124

AC:

5164

AN:

41498

American (AMR)

AF:

0.242

AC:

3704

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1392

AN:

3472

East Asian (EAS)

AF:

0.254

AC:

1310

AN:

5166

South Asian (SAS)

AF:

0.263

AC:

1265

AN:

4816

European-Finnish (FIN)

AF:

0.392

AC:

4130

AN:

10548

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.362

AC:

24591

AN:

67962

Other (OTH)

AF:

0.280

AC:

590

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1512

3025

4537

6050

7562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.334

Hom.:

16030

Bravo

AF:

0.263

Asia WGS

AF:

0.207

AC:

724

AN:

3478

EpiCase

AF:

0.369

EpiControl

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 45. Only high quality variants are reported. -

Dec 16, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.3

(source)

DANN

Benign

0.90

PhyloP100

-0.18

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over