rs6926723

Positions:

• chr6-30915026-G-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.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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=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 id is 380189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30915026-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.190G>A	p.Gly64Arg	missense_variant	2/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.280G>A	p.Gly94Arg	missense_variant	2/30		NP_001161206.1
VARS2	NM_001167733.3	c.-219-130G>A		intron_variant			NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.190G>A	p.Gly64Arg	missense_variant	2/30		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

GnomAD3 exomes AF: 0.0506 AC: 12562 AN: 248130 Hom.: 501 AF XY: 0.0467 AC XY: 6296 AN XY: 134852

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 SAS exome AF: 0.0339

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

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0966

Gnomad4 ASJ exome AF: 0.0895

Gnomad4 EAS exome AF: 0.0616

Gnomad4 SAS exome AF: 0.0335

Gnomad4 FIN exome AF: 0.00981

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0490

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

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0891

Gnomad4 ASJ AF: 0.0913

Gnomad4 EAS AF: 0.0632

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0422 Hom.: 353

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2015

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;.;.;.
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

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