6-30921612-T-C

Variant names:

• chr6-30921612-T-C
• rs2074511
• NM_020442.6:c.1656T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020442.6(VARS2):​c.1656T>C​(p.Val552Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,606,782 control chromosomes in the GnomAD database, including 39,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V552V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (4000 hom., cov: 32)
  • Exomes 𝑓: 0.19 (35175 hom.)
• Consequence: VARS2 NM_020442.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.45
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-30921612-T-C is Benign according to our data. Variant chr6-30921612-T-C is described in ClinVar as Benign. ClinVar VariationId is 380156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 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.1656T>C	p.Val552Val	synonymous	Exon 18 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.1746T>C	p.Val582Val	synonymous	Exon 18 of 30	NP_001161206.1
	VARS2	NM_001167733.3		c.1236T>C	p.Val412Val	synonymous	Exon 17 of 29	NP_001161205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.1656T>C	p.Val552Val	synonymous	Exon 18 of 30	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.1656T>C	p.Val552Val	synonymous	Exon 17 of 29	ENSP00000316092.5
	VARS2	ENST00000476162.5	TSL:1	n.514T>C		non_coding_transcript_exon	Exon 7 of 18

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30869 AN: 151860 Hom.: 3988 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.269 AC: 63022 AN: 233960 AF XY: 0.267

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.546

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.195 AC: 283500 AN: 1454804 Hom.: 35175 Cov.: 36 AF XY: 0.200 AC XY: 144322 AN XY: 723014

African (AFR) AF: 0.135 AC: 4519 AN: 33466

American (AMR) AF: 0.430 AC: 18710 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5806 AN: 25870

East Asian (EAS) AF: 0.555 AC: 21957 AN: 39552

South Asian (SAS) AF: 0.398 AC: 33750 AN: 84760

European-Finnish (FIN) AF: 0.242 AC: 12467 AN: 51472

Middle Eastern (MID) AF: 0.191 AC: 1100 AN: 5762

European-Non Finnish (NFE) AF: 0.155 AC: 171712 AN: 1110228

Other (OTH) AF: 0.224 AC: 13479 AN: 60206

GnomAD4 genome AF: 0.203 AC: 30902 AN: 151978 Hom.: 4000 Cov.: 32 AF XY: 0.214 AC XY: 15889 AN XY: 74250

African (AFR) AF: 0.142 AC: 5881 AN: 41448

American (AMR) AF: 0.329 AC: 5019 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3468

East Asian (EAS) AF: 0.574 AC: 2954 AN: 5148

South Asian (SAS) AF: 0.425 AC: 2049 AN: 4822

European-Finnish (FIN) AF: 0.240 AC: 2534 AN: 10544

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10977 AN: 67962

Other (OTH) AF: 0.201 AC: 425 AN: 2112

Alfa AF: 0.177 Hom.: 5330

Bravo AF: 0.203

Asia WGS AF: 0.501 AC: 1740 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.19
DANN	Benign	0.73
PhyloP100		-2.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	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: rs2074511; hg19: chr6-30889389; COSMIC: COSV58911919; COSMIC: COSV58911919;