6-30914857-C-T

Variant names:

• chr6-30914857-C-T
• rs1264302
• NM_020442.6:c.21C>T

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.21C>T​(p.Ala7Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,612,758 control chromosomes in the GnomAD database, including 93,516 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: 32)
  • Exomes 𝑓: 0.34 (86688 hom.)
• Consequence: VARS2 NM_020442.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.184
• Publications: 32 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=-0.63).
• BP6: Variant 6-30914857-C-T is Benign according to our data. Variant chr6-30914857-C-T is described in ClinVar as Benign. ClinVar VariationId is 380149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.21C>T	p.Ala7Ala	synonymous	Exon 2 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.111C>T	p.Ala37Ala	synonymous	Exon 2 of 30	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.-219-299C>T		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.21C>T	p.Ala7Ala	synonymous	Exon 2 of 30	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000321897.9	TSL:1	c.21C>T	p.Ala7Ala	synonymous	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000924208.1		c.21C>T	p.Ala7Ala	synonymous	Exon 2 of 30	ENSP00000594267.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42528 AN: 151942 Hom.: 6831 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.316 AC: 77929 AN: 246428 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: 0.369

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.339 AC: 495673 AN: 1460696 Hom.: 86688 Cov.: 60 AF XY: 0.339 AC XY: 246474 AN XY: 726678

African (AFR) AF: 0.116 AC: 3867 AN: 33480

American (AMR) AF: 0.220 AC: 9839 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9794 AN: 26136

East Asian (EAS) AF: 0.241 AC: 9552 AN: 39698

South Asian (SAS) AF: 0.276 AC: 23791 AN: 86254

European-Finnish (FIN) AF: 0.386 AC: 20172 AN: 52294

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

European-Non Finnish (NFE) AF: 0.358 AC: 397958 AN: 1111962

Other (OTH) AF: 0.311 AC: 18799 AN: 60382

GnomAD4 genome AF: 0.280 AC: 42538 AN: 152062 Hom.: 6828 Cov.: 32 AF XY: 0.281 AC XY: 20858 AN XY: 74316

African (AFR) AF: 0.124 AC: 5164 AN: 41498

American (AMR) AF: 0.242 AC: 3704 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3472

East Asian (EAS) AF: 0.254 AC: 1310 AN: 5166

South Asian (SAS) AF: 0.263 AC: 1265 AN: 4816

European-Finnish (FIN) AF: 0.392 AC: 4130 AN: 10548

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

European-Non Finnish (NFE) AF: 0.362 AC: 24591 AN: 67962

Other (OTH) AF: 0.280 AC: 590 AN: 2104

Alfa AF: 0.334 Hom.: 16030

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 724 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.372

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	-0.63
CADD	Benign	9.3
DANN	Benign	0.90
PhyloP100		-0.18
PromoterAI		0.018	Neutral
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: rs1264302; hg19: chr6-30882634; COSMIC: COSV52558947; COSMIC: COSV52558947;