6-30924387-CGC-TGT

Variant names:

• chr6-30924387-CGC-TGT
• NM_020442.6:c.2500_2502delCGCinsTGT
• VARS2 p.Arg834Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_020442.6(VARS2):​c.2500_2502delCGCinsTGT​(p.Arg834Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R834H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.869
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000288473 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2500_2502delCGCinsTGT	p.Arg834Cys	missense	N/A	NP_065175.4
	VARS2	NM_001167734.2		c.2590_2592delCGCinsTGT	p.Arg864Cys	missense	N/A	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.2080_2082delCGCinsTGT	p.Arg694Cys	missense	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.2500_2502delCGCinsTGT	p.Arg834Cys	missense	N/A	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000321897.9	TSL:1	c.2500_2502delCGCinsTGT	p.Arg834Cys	missense	N/A	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000476162.5	TSL:1	n.1287_1289delCGCinsTGT		non_coding_transcript_exon	Exon 14 of 18

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-30892164;