6-30914500-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000321897(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 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870

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]

ENSG00000288473 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.-28+156C>T		intron_variant	Intron 1 of 29	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.58+31C>T		intron_variant	Intron 1 of 29		NP_001161206.1
VARS2	NM_001167733.3	c.-220+156C>T		intron_variant	Intron 1 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.-28+156C>T		intron_variant	Intron 1 of 29		NM_020442.6	ENSP00000502585.1

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

GnomAD3 exomes AF: 0.312 AC: 5781 AN: 18528 Hom.: 967 AF XY: 0.317 AC XY: 3035 AN XY: 9578

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 SAS exome AF: 0.275

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

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.373

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.308

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

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.279

Alfa AF: 0.338 Hom.: 5652

Bravo AF: 0.263

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 45% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 42. Only high quality variants are reported. -

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.3
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1264305; hg19: chr6-30882277;