6-30918851-C-G

Variant names:

• chr6-30918851-C-G
• rs587777585
• NM_020442.6:c.1010C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_020442.6(VARS2):​c.1010C>G​(p.Thr337Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T337I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.12
• Publications: 12 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_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-30918851-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 141427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

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.1010C>G	p.Thr337Arg	missense	Exon 11 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.1100C>G	p.Thr367Arg	missense	Exon 11 of 30	NP_001161206.1	A0A1U9X9B3
	VARS2	NM_001167733.3		c.590C>G	p.Thr197Arg	missense	Exon 10 of 29	NP_001161205.1	Q5ST30-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.1010C>G	p.Thr337Arg	missense	Exon 11 of 30	ENSP00000502585.1	Q5ST30-1
	VARS2	ENST00000321897.9	TSL:1	c.1010C>G	p.Thr337Arg	missense	Exon 10 of 29	ENSP00000316092.5	Q5ST30-1
	VARS2	ENST00000924208.1		c.1025C>G	p.Thr342Arg	missense	Exon 11 of 30	ENSP00000594267.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.80		Loss of glycosylation at T337 (P = 0.0079)
MVP		0.69
MPC		1.4
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.99
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587777585; hg19: chr6-30886628;