chr6-30916659-A-G

Variant names:

• chr6-30916659-A-G
• rs1264298
• NM_020442.6:c.672-219A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020442.6(VARS2):​c.672-219A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 587,934 control chromosomes in the GnomAD database, including 32,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6828 hom., cov: 31)
  • Exomes 𝑓: 0.33 (25257 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.215
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-30916659-A-G is Benign according to our data. Variant chr6-30916659-A-G is described in ClinVar as Benign. ClinVar VariationId is 669590.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.672-219A>G		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.762-219A>G		intron	N/A	NP_001161206.1
	VARS2	NM_001167733.3		c.252-219A>G		intron	N/A	NP_001161205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.672-219A>G		intron	N/A	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.672-219A>G		intron	N/A	ENSP00000316092.5
	VARS2	ENST00000490699.1	TSL:3	n.232A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42481 AN: 151666 Hom.: 6831 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.254

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

GnomAD4 exome AF: 0.332 AC: 144653 AN: 436150 Hom.: 25257 Cov.: 4 AF XY: 0.330 AC XY: 75556 AN XY: 228954

African (AFR) AF: 0.121 AC: 1483 AN: 12244

American (AMR) AF: 0.226 AC: 3849 AN: 17002

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 4990 AN: 13380

East Asian (EAS) AF: 0.230 AC: 6988 AN: 30374

South Asian (SAS) AF: 0.276 AC: 11604 AN: 42052

European-Finnish (FIN) AF: 0.382 AC: 11583 AN: 30292

Middle Eastern (MID) AF: 0.318 AC: 679 AN: 2134

European-Non Finnish (NFE) AF: 0.363 AC: 95511 AN: 263304

Other (OTH) AF: 0.314 AC: 7966 AN: 25368

GnomAD4 genome AF: 0.280 AC: 42491 AN: 151784 Hom.: 6828 Cov.: 31 AF XY: 0.281 AC XY: 20830 AN XY: 74164

African (AFR) AF: 0.125 AC: 5157 AN: 41382

American (AMR) AF: 0.242 AC: 3694 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1392 AN: 3466

East Asian (EAS) AF: 0.253 AC: 1305 AN: 5150

South Asian (SAS) AF: 0.263 AC: 1264 AN: 4810

European-Finnish (FIN) AF: 0.392 AC: 4113 AN: 10484

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

European-Non Finnish (NFE) AF: 0.362 AC: 24586 AN: 67926

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

Alfa AF: 0.331 Hom.: 22867

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 725 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.3
DANN	Benign	0.47
PhyloP100		-0.21
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: rs1264298; hg19: chr6-30884436;