NM_020442.6:c.985+56A>G

Variant names:

• chr6-30917862-A-G
• rs9262288
• NM_020442.6:c.985+56A>G

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.985+56A>G 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 1,524,872 control chromosomes in the GnomAD database, including 88,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6832 hom., cov: 32)
  • Exomes 𝑓: 0.34 (81624 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70
• Publications: 11 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=-0.93).
• BP6: Variant 6-30917862-A-G is Benign according to our data. Variant chr6-30917862-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229689.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.985+56A>G		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.1075+56A>G		intron	N/A	NP_001161206.1
	VARS2	NM_001167733.3		c.565+56A>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.985+56A>G		intron	N/A	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.985+56A>G		intron	N/A	ENSP00000316092.5
	VARS2	ENST00000924208.1		c.1000+56A>G		intron	N/A	ENSP00000594267.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42546 AN: 151902 Hom.: 6835 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

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: 0.282

GnomAD4 exome AF: 0.340 AC: 466568 AN: 1372852 Hom.: 81624 AF XY: 0.339 AC XY: 230198 AN XY: 678684

African (AFR) AF: 0.116 AC: 3609 AN: 31032

American (AMR) AF: 0.224 AC: 7923 AN: 35434

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9369 AN: 25008

East Asian (EAS) AF: 0.235 AC: 8348 AN: 35574

South Asian (SAS) AF: 0.276 AC: 21732 AN: 78654

European-Finnish (FIN) AF: 0.384 AC: 18787 AN: 48874

Middle Eastern (MID) AF: 0.329 AC: 1853 AN: 5640

European-Non Finnish (NFE) AF: 0.357 AC: 377279 AN: 1055544

Other (OTH) AF: 0.309 AC: 17668 AN: 57092

GnomAD4 genome AF: 0.280 AC: 42556 AN: 152020 Hom.: 6832 Cov.: 32 AF XY: 0.281 AC XY: 20883 AN XY: 74302

African (AFR) AF: 0.125 AC: 5172 AN: 41476

American (AMR) AF: 0.242 AC: 3702 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1393 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1307 AN: 5158

South Asian (SAS) AF: 0.263 AC: 1263 AN: 4810

European-Finnish (FIN) AF: 0.393 AC: 4151 AN: 10568

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

European-Non Finnish (NFE) AF: 0.362 AC: 24588 AN: 67932

Other (OTH) AF: 0.279 AC: 590 AN: 2114

Alfa AF: 0.329 Hom.: 8302

Bravo AF: 0.263

Asia WGS AF: 0.208 AC: 726 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	-0.93
CADD	Benign	0.043
DANN	Benign	0.51
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs9262288; hg19: chr6-30885639; COSMIC: COSV52558958; COSMIC: COSV52558958;