6-30914638-C-T

Variant names:

• chr6-30914638-C-T
• rs1264304
• ENST00000321897.9:c.-199C>T

Variant summary

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

The ENST00000321897.9(VARS2):​c.-199C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,064,428 control chromosomes in the GnomAD database, including 8,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.075 (610 hom., cov: 32)
  • Exomes 𝑓: 0.12 (7814 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.71
• Publications: 20 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=-0.86).
• BP6: Variant 6-30914638-C-T is Benign according to our data. Variant chr6-30914638-C-T is described in ClinVar as Benign. ClinVar VariationId is 673366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000321897.9. 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.-27-172C>T		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.59-167C>T		intron	N/A	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.-220+294C>T		intron	N/A	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000321897.9	TSL:1	c.-199C>T		5_prime_UTR	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000676266.1	MANE Select	c.-27-172C>T		intron	N/A	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000672801.1		c.-199C>T		5_prime_UTR	Exon 1 of 29	ENSP00000500615.1	A0A0A0MTG1

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11342 AN: 152122 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.118 AC: 107956 AN: 912188 Hom.: 7814 Cov.: 12 AF XY: 0.117 AC XY: 53085 AN XY: 452834

African (AFR) AF: 0.0330 AC: 693 AN: 21020

American (AMR) AF: 0.0266 AC: 454 AN: 17052

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 752 AN: 16302

East Asian (EAS) AF: 0.00109 AC: 35 AN: 32242

South Asian (SAS) AF: 0.0684 AC: 3568 AN: 52180

European-Finnish (FIN) AF: 0.0778 AC: 2313 AN: 29726

Middle Eastern (MID) AF: 0.0400 AC: 178 AN: 4448

European-Non Finnish (NFE) AF: 0.137 AC: 95883 AN: 698020

Other (OTH) AF: 0.0990 AC: 4080 AN: 41198

GnomAD4 genome AF: 0.0747 AC: 11367 AN: 152240 Hom.: 610 Cov.: 32 AF XY: 0.0695 AC XY: 5171 AN XY: 74436

African (AFR) AF: 0.0333 AC: 1382 AN: 41532

American (AMR) AF: 0.0293 AC: 448 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3472

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5190

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4828

European-Finnish (FIN) AF: 0.0699 AC: 741 AN: 10596

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8108 AN: 68004

Other (OTH) AF: 0.0535 AC: 113 AN: 2114

Alfa AF: 0.107 Hom.: 2835

Bravo AF: 0.0694

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.83
PhyloP100		-2.7
PromoterAI		-0.076	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1264304; hg19: chr6-30882415;