6-30914850-C-A

Position:

• chr6-30914850-C-A

Variant summary

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

The NM_020442.6(VARS2):​c.14C>A​(p.Pro5His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.782

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=0.18997312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.14C>A	p.Pro5His	missense_variant	2/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.104C>A	p.Pro35His	missense_variant	2/30		NP_001161206.1
VARS2	NM_001167733.3	c.-219-306C>A		intron_variant			NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.14C>A	p.Pro5His	missense_variant	2/30		NM_020442.6	ENSP00000502585.1

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.104C>A (p.P35H) alteration is located in exon 2 (coding exon 2) of the VARS2 gene. This alteration results from a C to A substitution at nucleotide position 104, causing the proline (P) at amino acid position 35 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0029	T;T;.;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.030	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.28
MutPred		0.30		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);
MVP		0.72
MPC		0.95
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr6-30882627;