rs201503021

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006440.5(TXNRD2):c.858G>C(p.Arg286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.0150

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014597446).

BP6

Variant 22-19895498-C-G is Benign according to our data. Variant chr22-19895498-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414282.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr22-19895498-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5 link	c.858G>C	p.Arg286Ser	missense_variant	Exon 11 of 18	ENST00000400521.7	NP_006431.2	Q9NNW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 link	c.858G>C	p.Arg286Ser	missense_variant	Exon 11 of 18	1	NM_006440.5	ENSP00000383365.1		Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000634

AC:

158

AN:

249064

Hom.:

AF XY:

0.000718

AC XY:

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.0000935

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.00107

AC:

1557

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

788

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00126

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152216

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000670

Hom.:

Bravo

AF:

0.000740

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00118

AC:

ExAC

AF:

0.000644

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21247928) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1Benign:1

Aug 01, 2017

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TXNRD2-related disorder

Uncertain:1

Sep 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TXNRD2 c.858G>C variant is predicted to result in the amino acid substitution p.Arg286Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-19883021-C-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Benign:1

Dec 08, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

.;.;.;.;T;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.85

.;T;.;.;T;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.015

T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

.;.;.;.;M;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;.;N;N;N;.;N

REVEL

Benign

0.058

Sift

Uncertain

0.017

D;.;D;D;D;.;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D;D

Polyphen

0.44, 0.72

.;.;.;.;B;.;P

Vest4

0.14

MutPred

0.48

.;.;.;.;Loss of MoRF binding (P = 0.0207);.;Loss of MoRF binding (P = 0.0207);

MVP

0.43

MPC

0.24

ClinPred

0.018

GERP RS

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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