6-30914433-C-A

Variant names:

• chr6-30914433-C-A
• rs948200308
• ENST00000321897:c.-404C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001167734.2(VARS2):​c.22C>A​(p.Arg8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,271,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: VARS2 NM_001167734.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.605

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092660695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.-28+89C>A		intron_variant	Intron 1 of 29	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.22C>A	p.Arg8Ser	missense_variant	Exon 1 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.-220+89C>A		intron_variant	Intron 1 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.-28+89C>A		intron_variant	Intron 1 of 29		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 4 AN: 1119630 Hom.: 0 Cov.: 37 AF XY: 0.00000564 AC XY: 3 AN XY: 532266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000424

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.91	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.068
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.20
MutPred		0.39		Gain of glycosylation at R8 (P = 0.0209);
MVP		0.055
MPC		0.97
ClinPred		0.60	D
GERP RS		-0.56
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
gMVP		0.27

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: rs948200308; hg19: chr6-30882210;