rs55865499

chr6-30923211-G-Achr6-30923211-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020442.6(VARS2):c.2293G>A(p.Val765Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,612,664 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.249

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049292743).
• BP6: Variant 6-30923211-G-A is Benign according to our data. Variant chr6-30923211-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377004.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00258 (393/152340) while in subpopulation NFE AF= 0.00342 (233/68030). AF 95% confidence interval is 0.00306. There are 2 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.2293G>A	p.Val765Met	missense_variant	24/30	ENST00000676266.1
VARS2	NM_001167734.2	c.2383G>A	p.Val795Met	missense_variant	24/30
VARS2	NM_001167733.3	c.1873G>A	p.Val625Met	missense_variant	23/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.2293G>A	p.Val765Met	missense_variant	24/30		NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00275 AC: 677 AN: 246580 Hom.: 0 AF XY: 0.00253 AC XY: 340 AN XY: 134414

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00264 AC: 3860 AN: 1460324 Hom.: 8 Cov.: 33 AF XY: 0.00261 AC XY: 1899 AN XY: 726400

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.00260 AC XY: 194 AN XY: 74504

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00342

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.00351 AC: 19

ExAC AF: 0.00269 AC: 317

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	VARS2: PM2, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.024	T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.72	N;.;N
REVEL	Benign	0.022
Sift	Benign	0.047	D;.;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.11	B;.;.
Vest4		0.16
MVP		0.22
MPC		0.70
ClinPred		0.020	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.13

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: rs55865499; hg19: chr6-30890988; COSMIC: COSV58913391;