6-30922706-G-T

Variant names:

• chr6-30922706-G-T
• rs2074506
• NM_020442.6:c.2038G>T

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.2038G>T​(p.Val680Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.334 in 1,611,656 control chromosomes in the GnomAD database, including 93,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6844 hom., cov: 33)
  • Exomes 𝑓: 0.34 (86665 hom.)
• Consequence: VARS2 NM_020442.6 missense, splice_region
• Scores: Splicing: ADA: 0.9522
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.29
• Publications: 46 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=0.0024447143).
• BP6: Variant 6-30922706-G-T is Benign according to our data. Variant chr6-30922706-G-T is described in ClinVar as Benign. ClinVar VariationId is 380157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020442.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.2038G>T	p.Val680Leu	missense splice_region	Exon 22 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.2128G>T	p.Val710Leu	missense splice_region	Exon 22 of 30	NP_001161206.1
	VARS2	NM_001167733.3		c.1618G>T	p.Val540Leu	missense splice_region	Exon 21 of 29	NP_001161205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.2038G>T	p.Val680Leu	missense splice_region	Exon 22 of 30	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.2038G>T	p.Val680Leu	missense splice_region	Exon 21 of 29	ENSP00000316092.5
	VARS2	ENST00000476162.5	TSL:1	n.825G>T		splice_region non_coding_transcript_exon	Exon 10 of 18

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42592 AN: 152058 Hom.: 6847 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.316 AC: 77549 AN: 245306 AF XY: 0.324

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.339 AC: 495350 AN: 1459482 Hom.: 86665 Cov.: 52 AF XY: 0.339 AC XY: 246296 AN XY: 726010

African (AFR) AF: 0.115 AC: 3864 AN: 33464

American (AMR) AF: 0.220 AC: 9807 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9759 AN: 26050

East Asian (EAS) AF: 0.241 AC: 9551 AN: 39688

South Asian (SAS) AF: 0.276 AC: 23762 AN: 86080

European-Finnish (FIN) AF: 0.386 AC: 20169 AN: 52284

Middle Eastern (MID) AF: 0.330 AC: 1898 AN: 5756

European-Non Finnish (NFE) AF: 0.358 AC: 397736 AN: 1111250

Other (OTH) AF: 0.312 AC: 18804 AN: 60308

GnomAD4 genome AF: 0.280 AC: 42601 AN: 152174 Hom.: 6844 Cov.: 33 AF XY: 0.281 AC XY: 20908 AN XY: 74384

African (AFR) AF: 0.125 AC: 5177 AN: 41550

American (AMR) AF: 0.242 AC: 3706 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1393 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1314 AN: 5182

South Asian (SAS) AF: 0.263 AC: 1270 AN: 4822

European-Finnish (FIN) AF: 0.393 AC: 4152 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24615 AN: 67970

Other (OTH) AF: 0.277 AC: 584 AN: 2106

Alfa AF: 0.338 Hom.: 40170

Bravo AF: 0.263

TwinsUK AF: 0.355 AC: 1317

ALSPAC AF: 0.368 AC: 1419

ESP6500AA AF: 0.146 AC: 440

ESP6500EA AF: 0.377 AC: 2039

ExAC AF: 0.319 AC: 37430

Asia WGS AF: 0.207 AC: 725 AN: 3476

EpiCase AF: 0.369

EpiControl AF: 0.372

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Combined oxidative phosphorylation defect type 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0035	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.034
Sift	Benign	0.14	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.070
MutPred		0.15		Gain of catalytic residue at V680 (P = 0.0579)
MPC		0.50
ClinPred		0.0041	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.27
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.85
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs2074506; hg19: chr6-30890483; COSMIC: COSV58911557; COSMIC: COSV58911557;