rs9394021

Variant names:

• chr6-30925350-G-A
• rs9394021
• NM_020442.6:c.2750G>A

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000288473 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes AF: 0.294 AC: 71014 AN: 241804 Hom.: 13202 AF XY: 0.291 AC XY: 38502 AN XY: 132374

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 SAS exome AF: 0.454

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

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.564

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.247

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

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.497

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.242

Alfa AF: 0.196 Hom.: 4171

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

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. -

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. -

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;.;.
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
Polyphen		1.0	D;.;.
Vest4		0.18
MPC		0.72
ClinPred		0.070	T
GERP RS		5.4
Varity_R		0.65
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs9394021; hg19: chr6-30893127; COSMIC: COSV58911057; COSMIC: COSV58911057;