rs2517467

Variant names:

• chr6-30921483-G-A
• rs2517467
• NM_020442.6:c.1633-106G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-30921483-G-A
• chr6-30921483-G-C
• chr6-30921483-G-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.1633-106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,442,894 control chromosomes in the GnomAD database, including 218,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21794 hom., cov: 32)
  • Exomes 𝑓: 0.54 (196247 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.764
• Publications: 27 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=-0.89).
• BP6: Variant 6-30921483-G-A is Benign according to our data. Variant chr6-30921483-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 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.1633-106G>A		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.1723-106G>A		intron	N/A	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.1213-106G>A		intron	N/A	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.1633-106G>A		intron	N/A	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000321897.9	TSL:1	c.1633-106G>A		intron	N/A	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000476162.5	TSL:1	n.491-106G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79239 AN: 151908 Hom.: 21779 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.544 AC: 701678 AN: 1290868 Hom.: 196247 Cov.: 20 AF XY: 0.550 AC XY: 353011 AN XY: 642332

African (AFR) AF: 0.343 AC: 10255 AN: 29906

American (AMR) AF: 0.665 AC: 23645 AN: 35556

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 15101 AN: 24466

East Asian (EAS) AF: 0.803 AC: 28579 AN: 35592

South Asian (SAS) AF: 0.730 AC: 56297 AN: 77124

European-Finnish (FIN) AF: 0.638 AC: 29263 AN: 45884

Middle Eastern (MID) AF: 0.576 AC: 3165 AN: 5496

European-Non Finnish (NFE) AF: 0.514 AC: 505160 AN: 982402

Other (OTH) AF: 0.555 AC: 30213 AN: 54442

GnomAD4 genome AF: 0.522 AC: 79289 AN: 152026 Hom.: 21794 Cov.: 32 AF XY: 0.534 AC XY: 39670 AN XY: 74328

African (AFR) AF: 0.366 AC: 15172 AN: 41422

American (AMR) AF: 0.602 AC: 9192 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2214 AN: 3472

East Asian (EAS) AF: 0.843 AC: 4353 AN: 5166

South Asian (SAS) AF: 0.760 AC: 3668 AN: 4826

European-Finnish (FIN) AF: 0.644 AC: 6811 AN: 10578

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36052 AN: 67964

Other (OTH) AF: 0.521 AC: 1102 AN: 2114

Alfa AF: 0.527 Hom.: 54741

Bravo AF: 0.508

Asia WGS AF: 0.749 AC: 2607 AN: 3478

ClinVar

ClinVar submissions

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	-0.89
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-0.76
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)		0.040		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: rs2517467; hg19: chr6-30889260;