NM_020442.6:c.190G>A

Variant names:

• chr6-30915026-G-A
• rs6926723
• NM_020442.6:c.190G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020442.6(VARS2):​c.190G>A​(p.Gly64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,613,386 control chromosomes in the GnomAD database, including 2,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (506 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1507 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.714
• Publications: 23 publications found

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)

ENSG00000288473 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015696287).
• BP6: Variant 6-30915026-G-A is Benign according to our data. Variant chr6-30915026-G-A is described in ClinVar as Benign. ClinVar VariationId is 380189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.280G>A	p.Gly94Arg	missense_variant	Exon 2 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.-219-130G>A		intron_variant	Intron 1 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9829 AN: 152124 Hom.: 504 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0891

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0660

GnomAD2 exomes AF: 0.0506 AC: 12562 AN: 248130 AF XY: 0.0467

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0992

Gnomad ASJ exome AF: 0.0930

Gnomad EAS exome AF: 0.0627

Gnomad FIN exome AF: 0.00925

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0365 AC: 53278 AN: 1461144 Hom.: 1507 Cov.: 36 AF XY: 0.0362 AC XY: 26295 AN XY: 726924

African (AFR) AF: 0.133 AC: 4443 AN: 33380

American (AMR) AF: 0.0966 AC: 4313 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0895 AC: 2340 AN: 26132

East Asian (EAS) AF: 0.0616 AC: 2447 AN: 39700

South Asian (SAS) AF: 0.0335 AC: 2885 AN: 86224

European-Finnish (FIN) AF: 0.00981 AC: 520 AN: 53012

Middle Eastern (MID) AF: 0.0596 AC: 344 AN: 5768

European-Non Finnish (NFE) AF: 0.0297 AC: 33027 AN: 1111918

Other (OTH) AF: 0.0490 AC: 2959 AN: 60378

GnomAD4 genome AF: 0.0646 AC: 9842 AN: 152242 Hom.: 506 Cov.: 32 AF XY: 0.0638 AC XY: 4751 AN XY: 74422

African (AFR) AF: 0.126 AC: 5245 AN: 41542

American (AMR) AF: 0.0891 AC: 1363 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 317 AN: 3472

East Asian (EAS) AF: 0.0632 AC: 327 AN: 5172

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4828

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2168 AN: 68012

Other (OTH) AF: 0.0649 AC: 137 AN: 2112

Alfa AF: 0.0444 Hom.: 804

Bravo AF: 0.0748

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.117 AC: 354

ESP6500EA AF: 0.0353 AC: 191

ExAC AF: 0.0484 AC: 5866

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0366

EpiControl AF: 0.0371

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.62
DANN	Benign	0.80
DEOGEN2	Benign	0.0034	T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.31	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		-0.71
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.026
MutPred		0.12		Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);.;Gain of MoRF binding (P = 0.0157);
MPC		0.54
ClinPred		0.0061	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.18
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6926723; hg19: chr6-30882803; COSMIC: COSV52558737; COSMIC: COSV52558737;