6-30923094-T-C

Variant names:

• chr6-30923094-T-C
• rs753725
• NM_020442.6:c.2186-10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020442.6(VARS2):​c.2186-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 1,612,430 control chromosomes in the GnomAD database, including 246,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21774 hom., cov: 32)
  • Exomes 𝑓: 0.55 (224372 hom.)
• Consequence: VARS2 NM_020442.6 intron
• Scores: Splicing: ADA: 0.0001184
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00800
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000288473 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-30923094-T-C is Benign according to our data. Variant chr6-30923094-T-C is described in ClinVar as Benign. ClinVar VariationId is 380159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.2186-10T>C		intron_variant	Intron 23 of 29	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.2276-10T>C		intron_variant	Intron 23 of 29		NP_001161206.1
VARS2	NM_001167733.3	c.1766-10T>C		intron_variant	Intron 22 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.2186-10T>C		intron_variant	Intron 23 of 29		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79191 AN: 151894 Hom.: 21759 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.609 AC: 149847 AN: 246174 AF XY: 0.614

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.846

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.547 AC: 799322 AN: 1460418 Hom.: 224372 Cov.: 76 AF XY: 0.553 AC XY: 401913 AN XY: 726496

African (AFR) AF: 0.345 AC: 11546 AN: 33476

American (AMR) AF: 0.674 AC: 30120 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 16135 AN: 26124

East Asian (EAS) AF: 0.805 AC: 31949 AN: 39692

South Asian (SAS) AF: 0.732 AC: 63128 AN: 86250

European-Finnish (FIN) AF: 0.640 AC: 33429 AN: 52228

Middle Eastern (MID) AF: 0.577 AC: 3326 AN: 5764

European-Non Finnish (NFE) AF: 0.518 AC: 575974 AN: 1111802

Other (OTH) AF: 0.558 AC: 33715 AN: 60372

GnomAD4 genome AF: 0.521 AC: 79241 AN: 152012 Hom.: 21774 Cov.: 32 AF XY: 0.533 AC XY: 39627 AN XY: 74308

African (AFR) AF: 0.366 AC: 15174 AN: 41438

American (AMR) AF: 0.601 AC: 9190 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2213 AN: 3466

East Asian (EAS) AF: 0.842 AC: 4340 AN: 5152

South Asian (SAS) AF: 0.761 AC: 3661 AN: 4810

European-Finnish (FIN) AF: 0.642 AC: 6795 AN: 10576

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36042 AN: 67964

Other (OTH) AF: 0.521 AC: 1101 AN: 2114

Alfa AF: 0.535 Hom.: 93929

Bravo AF: 0.508

Asia WGS AF: 0.749 AC: 2607 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 90% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 84. Only high quality variants are reported. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Combined oxidative phosphorylation defect type 20 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.48
PhyloP100		0.0080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs753725; hg19: chr6-30890871;