chr6-30922706-G-C

Variant names:

• chr6-30922706-G-C
• NM_020442.6:c.2038G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020442.6(VARS2):​c.2038G>C​(p.Val680Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VARS2 NM_020442.6 missense, splice_region
• Scores: Splicing: ADA: 0.9356
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36521894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.2038G>C	p.Val680Leu	missense_variant, splice_region_variant	Exon 22 of 30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.2128G>C	p.Val710Leu	missense_variant, splice_region_variant	Exon 22 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.1618G>C	p.Val540Leu	missense_variant, splice_region_variant	Exon 21 of 29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.2038G>C	p.Val680Leu	missense_variant, splice_region_variant	Exon 22 of 30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0035	T;.;.
Eigen	Benign	0.029
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.27	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.035
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.070
MutPred		0.15		Gain of catalytic residue at V680 (P = 0.0579);.;.;
MVP		0.50
MPC		0.50
ClinPred		0.60	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-30890483;