6-30923211-G-C

Position:

• chr6-30923211-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020442.6(VARS2):​c.2293G>C​(p.Val765Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. V765M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039625704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.2293G>C	p.Val765Leu	missense_variant	24/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.2383G>C	p.Val795Leu	missense_variant	24/30		NP_001161206.1
VARS2	NM_001167733.3	c.1873G>C	p.Val625Leu	missense_variant	23/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.2293G>C	p.Val765Leu	missense_variant	24/30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.2
DANN	Benign	0.81
DEOGEN2	Benign	0.0036	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.90	N;.;N
REVEL	Benign	0.025
Sift	Benign	0.22	T;.;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.12
MutPred		0.23		Gain of glycosylation at P768 (P = 0.1232);.;.;
MVP		0.15
MPC		0.44
ClinPred		0.060	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs55865499; hg19: chr6-30890988;