rs180876642

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000400521.7(TXNRD2):c.762C>T(p.Arg254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,557,794 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R254R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

TXNRD2
ENST00000400521.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.786

Variant links:

Genes affected

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

TXNRD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 22-19898051-G-A is Benign according to our data. Variant chr22-19898051-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 454288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19898051-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.786 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.762C>T	p.Arg254=	synonymous_variant	10/18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.762C>T	p.Arg254=	synonymous_variant	10/18	1	NM_006440.5	ENSP00000383365	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00101

AC:

165

AN:

164122

Hom.:

AF XY:

0.000948

AC XY:

AN XY:

87526

show subpopulations

Gnomad AFR exome

AF:

0.000345

Gnomad AMR exome

AF:

0.0000780

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00197

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00415

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.00111

AC:

1564

AN:

1405422

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

733

AN XY:

693978

show subpopulations

Gnomad4 AFR exome

AF:

0.000157

Gnomad4 AMR exome

AF:

0.000109

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00172

Gnomad4 SAS exome

AF:

0.0000377

Gnomad4 FIN exome

AF:

0.00452

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000737

GnomAD4 genome

AF:

0.000984

AC:

150

AN:

152372

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00527

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000644

Hom.:

Bravo

AF:

0.000623

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.7

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over