6-30914500-C-T

Variant names:

• chr6-30914500-C-T
• rs1264305
• ENST00000321897.9:c.-337C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000321897.9(VARS2):​c.-337C>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 0.336 in 1,329,760 control chromosomes in the GnomAD database, including 77,967 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 (71139 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870
• Publications: 28 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=-0.85).
• BP6: Variant 6-30914500-C-T is Benign according to our data. Variant chr6-30914500-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271839.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: 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.-28+156C>T		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.58+31C>T		intron	N/A	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.-220+156C>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.-337C>T		5_prime_UTR	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000676266.1	MANE Select	c.-28+156C>T		intron	N/A	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000672801.1		c.-337C>T		5_prime_UTR	Exon 1 of 29	ENSP00000500615.1	A0A0A0MTG1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42530 AN: 151948 Hom.: 6831 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.281

GnomAD2 exomes AF: 0.312 AC: 5781 AN: 18528 AF XY: 0.317

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.343 AC: 404390 AN: 1177694 Hom.: 71139 Cov.: 34 AF XY: 0.343 AC XY: 193490 AN XY: 564554

African (AFR) AF: 0.115 AC: 2778 AN: 24234

American (AMR) AF: 0.234 AC: 2760 AN: 11788

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 6077 AN: 16272

East Asian (EAS) AF: 0.227 AC: 6575 AN: 29006

South Asian (SAS) AF: 0.279 AC: 11436 AN: 41012

European-Finnish (FIN) AF: 0.386 AC: 10123 AN: 26246

Middle Eastern (MID) AF: 0.331 AC: 1606 AN: 4854

European-Non Finnish (NFE) AF: 0.357 AC: 348116 AN: 975912

Other (OTH) AF: 0.308 AC: 14919 AN: 48370

GnomAD4 genome AF: 0.280 AC: 42540 AN: 152066 Hom.: 6828 Cov.: 32 AF XY: 0.281 AC XY: 20881 AN XY: 74348

African (AFR) AF: 0.124 AC: 5167 AN: 41504

American (AMR) AF: 0.242 AC: 3708 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1303 AN: 5150

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4822

European-Finnish (FIN) AF: 0.392 AC: 4152 AN: 10586

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

European-Non Finnish (NFE) AF: 0.362 AC: 24569 AN: 67920

Other (OTH) AF: 0.279 AC: 590 AN: 2116

Alfa AF: 0.324 Hom.: 21367

Bravo AF: 0.263

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	-0.85
CADD	Benign	6.3
DANN	Benign	0.81
PhyloP100		-0.087
PromoterAI		-0.025	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1264305; hg19: chr6-30882277;