rs9394021

Variant names:

• chr6-30925350-G-A
• rs9394021
• NM_020442.6:c.2750G>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.2750G>A​(p.Arg917Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,611,106 control chromosomes in the GnomAD database, including 45,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5292 hom., cov: 33)
  • Exomes 𝑓: 0.21 (40659 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.27
• Publications: 32 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=3.0186772E-4).
• BP6: Variant 6-30925350-G-A is Benign according to our data. Variant chr6-30925350-G-A is described in ClinVar as Benign. ClinVar VariationId is 380161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.2750G>A	p.Arg917Gln	missense_variant	Exon 27 of 30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.2840G>A	p.Arg947Gln	missense_variant	Exon 27 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.2330G>A	p.Arg777Gln	missense_variant	Exon 26 of 29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.2750G>A	p.Arg917Gln	missense_variant	Exon 27 of 30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36668 AN: 152074 Hom.: 5278 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.294 AC: 71014 AN: 241804 AF XY: 0.291

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.563

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.208 AC: 303230 AN: 1458914 Hom.: 40659 Cov.: 34 AF XY: 0.214 AC XY: 155213 AN XY: 725604

African (AFR) AF: 0.229 AC: 7671 AN: 33464

American (AMR) AF: 0.454 AC: 20171 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6332 AN: 26068

East Asian (EAS) AF: 0.564 AC: 22361 AN: 39628

South Asian (SAS) AF: 0.456 AC: 39272 AN: 86126

European-Finnish (FIN) AF: 0.254 AC: 13254 AN: 52142

Middle Eastern (MID) AF: 0.247 AC: 1425 AN: 5760

European-Non Finnish (NFE) AF: 0.160 AC: 177874 AN: 1110994

Other (OTH) AF: 0.247 AC: 14870 AN: 60290

GnomAD4 genome AF: 0.241 AC: 36708 AN: 152192 Hom.: 5292 Cov.: 33 AF XY: 0.252 AC XY: 18769 AN XY: 74402

African (AFR) AF: 0.242 AC: 10033 AN: 41542

American (AMR) AF: 0.358 AC: 5480 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3468

East Asian (EAS) AF: 0.588 AC: 3040 AN: 5166

South Asian (SAS) AF: 0.497 AC: 2395 AN: 4822

European-Finnish (FIN) AF: 0.250 AC: 2653 AN: 10606

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11447 AN: 67988

Other (OTH) AF: 0.242 AC: 511 AN: 2110

Alfa AF: 0.198 Hom.: 11209

Bravo AF: 0.245

TwinsUK AF: 0.153 AC: 569

ALSPAC AF: 0.152 AC: 587

ESP6500AA AF: 0.232 AC: 700

ESP6500EA AF: 0.162 AC: 879

ExAC AF: 0.281 AC: 32889

Asia WGS AF: 0.541 AC: 1877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 22, 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.

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 59% 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: 55. Only high quality variants are reported.

Combined oxidative phosphorylation defect type 20 Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 23, 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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.00030	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.9	H;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.049	D;T;D
Vest4		0.18
ClinPred		0.070	T
GERP RS		5.4
Varity_R		0.65
gMVP		0.86
Mutation Taster		=90/10	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: rs9394021; hg19: chr6-30893127; COSMIC: COSV58911057; COSMIC: COSV58911057;