22-19877157-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_006440.5(TXNRD2):c.1523G>A(p.Arg508His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,609,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R508C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.455

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial glucocorticoid deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
glucocorticoid deficiency 5
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TXNRD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00671497).

BP6

Variant 22-19877157-C-T is Benign according to our data. Variant chr22-19877157-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5 link	c.1523G>A	p.Arg508His	missense_variant	Exon 17 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.1523G>A	p.Arg508His	missense_variant	Exon 17 of 18	1	NM_006440.5	ENSP00000383365.1		Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000234

AC:

AN:

247650

AF XY:

0.000156

show subpopulations

Gnomad AFR exome

AF:

0.00352

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000967

AC:

141

AN:

1457800

Hom.:

Cov.:

AF XY:

0.0000814

AC XY:

AN XY:

724642

show subpopulations

African (AFR)

AF:

0.00332

AC:

111

AN:

33424

American (AMR)

AF:

0.0000896

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52530

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

1109432

Other (OTH)

AF:

0.000249

AC:

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000907

AC:

138

AN:

152192

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00304

AC:

126

AN:

41510

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000949

Hom.:

Bravo

AF:

0.00139

ESP6500AA

AF:

0.00429

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000314

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 28, 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. -

TXNRD2-related disorder

Benign:1

Jul 27, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.32

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

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

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

PhyloP100

0.46

PrimateAI

Benign

0.27

PROVEAN

Benign

0.88

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

REVEL

Benign

0.042

Sift

Benign

0.38

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

Sift4G

Benign

0.32

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

Polyphen

0.0040

.;.;.;.;.;B;.

Vest4

0.10

MVP

0.59

MPC

0.25

ClinPred

0.017

GERP RS

1.7

Varity_R

0.028

Mutation Taster

=96/4

polymorphism

(source)

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

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22-19877157-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over