6-30918813-A-G

Position:

• chr6-30918813-A-G

Variant summary

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

The NM_020442.6(VARS2):​c.986-14A>G variant causes a splice polypyrimidine tract, intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VARS2 NM_020442.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.503

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.986-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000676266.1	NP_065175.4
VARS2	NM_001167733.3	c.566-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001161205.1
VARS2	NM_001167734.2	c.1076-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001161206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.986-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NM_020442.6	ENSP00000502585	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

May 04, 2017

This variant was found in trans with another variant (p.A420T) in a 6-year-old male with severe neurodevelopmental impairment, encephalopathy, microcephaly, hypertrophic cardiomyopathy, lactic acidosis, seizure disorder (infantile spasms), abnormal MRI showing brain and brainstem atrophy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.0
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: 14

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

Publications

LitVar

Other links and lift over

dbSNP: rs1297230026; hg19: chr6-30886590;