6-30914912-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020442.6(VARS2):c.76C>T(p.His26Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,613,038 control chromosomes in the GnomAD database, including 2,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.065 (501 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1509 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.146

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018354058).
• BP6: Variant 6-30914912-C-T is Benign according to our data. Variant chr6-30914912-C-T is described in ClinVar as [Benign]. Clinvar id is 380188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30914912-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.76C>T	p.His26Tyr	missense_variant	2/30	ENST00000676266.1
VARS2	NM_001167734.2	c.166C>T	p.His56Tyr	missense_variant	2/30
VARS2	NM_001167733.3	c.-219-244C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.76C>T	p.His26Tyr	missense_variant	2/30		NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9828 AN: 152150 Hom.: 499 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0891

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0660

GnomAD3 exomes AF: 0.0507 AC: 12514 AN: 246594 Hom.: 502 AF XY: 0.0467 AC XY: 6274 AN XY: 134420

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0993

Gnomad ASJ exome AF: 0.0929

Gnomad EAS exome AF: 0.0629

Gnomad SAS exome AF: 0.0342

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0365 AC: 53338 AN: 1460770 Hom.: 1509 Cov.: 62 AF XY: 0.0362 AC XY: 26328 AN XY: 726704

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0967

Gnomad4 ASJ exome AF: 0.0896

Gnomad4 EAS exome AF: 0.0617

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.00983

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0646 AC: 9841 AN: 152268 Hom.: 501 Cov.: 32 AF XY: 0.0638 AC XY: 4750 AN XY: 74440

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0891

Gnomad4 ASJ AF: 0.0911

Gnomad4 EAS AF: 0.0636

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0648

Alfa AF: 0.0424 Hom.: 375

Bravo AF: 0.0749

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.121 AC: 365

ESP6500EA AF: 0.0360 AC: 195

ExAC AF: 0.0478 AC: 5683

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0366

EpiControl AF: 0.0371

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.5
Dann	Benign	0.97
DEOGEN2	Benign	0.0031	T;T;.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.55	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.022	B;.;.;.
Vest4		0.042
MPC		0.52
ClinPred		0.0032	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6926224; hg19: chr6-30882689;