rs1264304

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-30914638-C-A
• chr6-30914638-C-G
• chr6-30914638-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000321897.9(VARS2):​c.-199C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000011 in 913,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.71
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

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>A		intron	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.59-167C>A		intron	N/A	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.-220+294C>A		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>A		5_prime_UTR	Exon 1 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000676266.1	MANE Select	c.-27-172C>A		intron	N/A	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000672801.1		c.-199C>A		5_prime_UTR	Exon 1 of 29	ENSP00000500615.1	A0A0A0MTG1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000110 AC: 1 AN: 913184 Hom.: 0 Cov.: 12 AF XY: 0.00000221 AC XY: 1 AN XY: 453322

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21026

American (AMR) AF: 0.00 AC: 0 AN: 17054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16304

East Asian (EAS) AF: 0.00 AC: 0 AN: 32242

South Asian (SAS) AF: 0.00 AC: 0 AN: 52200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4448

European-Non Finnish (NFE) AF: 0.00000143 AC: 1 AN: 698944

Other (OTH) AF: 0.00 AC: 0 AN: 41232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.55
DANN	Benign	0.63
PhyloP100		-2.7
PromoterAI		-0.13	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;