6-30926054-G-A

Variant names:

• chr6-30926054-G-A
• rs2532938
• NM_020442.6:c.3090+46G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167734.2(VARS2):​c.3180+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,612,636 control chromosomes in the GnomAD database, including 93,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6836 hom., cov: 33)
  • Exomes 𝑓: 0.34 (86675 hom.)
• Consequence: VARS2 NM_001167734.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.54
• Publications: 19 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 (BayesDel_noAF=-0.85).
• BP6: Variant 6-30926054-G-A is Benign according to our data. Variant chr6-30926054-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292282.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_001167734.2. 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.3090+46G>A		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.3180+46G>A		intron	N/A	NP_001161206.1
	VARS2	NM_001167733.3		c.2670+46G>A		intron	N/A	NP_001161205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.3090+46G>A		intron	N/A	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.3090+46G>A		intron	N/A	ENSP00000316092.5
	VARS2	ENST00000476162.5	TSL:1	n.1877+46G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42555 AN: 152038 Hom.: 6839 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.316 AC: 77861 AN: 246172 AF XY: 0.324

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.339 AC: 495623 AN: 1460480 Hom.: 86675 Cov.: 63 AF XY: 0.339 AC XY: 246421 AN XY: 726516

African (AFR) AF: 0.115 AC: 3864 AN: 33474

American (AMR) AF: 0.220 AC: 9839 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9788 AN: 26126

East Asian (EAS) AF: 0.241 AC: 9553 AN: 39696

South Asian (SAS) AF: 0.276 AC: 23787 AN: 86252

European-Finnish (FIN) AF: 0.386 AC: 20174 AN: 52302

Middle Eastern (MID) AF: 0.330 AC: 1901 AN: 5768

European-Non Finnish (NFE) AF: 0.358 AC: 397917 AN: 1111780

Other (OTH) AF: 0.311 AC: 18800 AN: 60370

GnomAD4 genome AF: 0.280 AC: 42565 AN: 152156 Hom.: 6836 Cov.: 33 AF XY: 0.281 AC XY: 20883 AN XY: 74378

African (AFR) AF: 0.125 AC: 5170 AN: 41524

American (AMR) AF: 0.242 AC: 3702 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1389 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1307 AN: 5166

South Asian (SAS) AF: 0.263 AC: 1270 AN: 4830

European-Finnish (FIN) AF: 0.392 AC: 4146 AN: 10582

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

European-Non Finnish (NFE) AF: 0.362 AC: 24600 AN: 67976

Other (OTH) AF: 0.279 AC: 589 AN: 2110

Alfa AF: 0.331 Hom.: 21824

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 725 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.059
DANN	Benign	0.54
PhyloP100		-2.5
Mutation Taster		=100/0	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: rs2532938; hg19: chr6-30893831; COSMIC: COSV58915042; COSMIC: COSV58915042;