rs5748469

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006440.5(TXNRD2):c.196G>T(p.Ala66Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,560,344 control chromosomes in the GnomAD database, including 123,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A66A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.37 ( 11774 hom., cov: 29)

Exomes 𝑓: 0.38 ( 112225 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.82

Publications

63 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.981186E-6).

BP6

Variant 22-19919576-C-A is Benign according to our data. Variant chr22-19919576-C-A is described in ClinVar as Benign. ClinVar VariationId is 263343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5 link	c.196G>T	p.Ala66Ser	missense_variant	Exon 3 of 18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 link	c.196G>T	p.Ala66Ser	missense_variant	Exon 3 of 18	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56077

AN:

151572

Hom.:

11759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.862

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.449

AC:

77201

AN:

172046

AF XY:

0.442

show subpopulations

Gnomad AFR exome

AF:

0.226

Gnomad AMR exome

AF:

0.612

Gnomad ASJ exome

AF:

0.420

Gnomad EAS exome

AF:

0.856

Gnomad FIN exome

AF:

0.476

Gnomad NFE exome

AF:

0.336

Gnomad OTH exome

AF:

0.424

GnomAD4 exome

AF:

0.385

AC:

541818

AN:

1408654

Hom.:

112225

Cov.:

AF XY:

0.388

AC XY:

270033

AN XY:

696196

show subpopulations

African (AFR)

AF:

0.228

AC:

7284

AN:

32008

American (AMR)

AF:

0.597

AC:

21989

AN:

36802

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

10695

AN:

25230

East Asian (EAS)

AF:

0.853

AC:

30697

AN:

35980

South Asian (SAS)

AF:

0.508

AC:

40478

AN:

79742

European-Finnish (FIN)

AF:

0.468

AC:

23413

AN:

49980

Middle Eastern (MID)

AF:

0.347

AC:

1981

AN:

5706

European-Non Finnish (NFE)

AF:

0.352

AC:

381499

AN:

1084768

Other (OTH)

AF:

0.407

AC:

23782

AN:

58438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

18452

36904

55355

73807

92259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12468

24936

37404

49872

62340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.370

AC:

56120

AN:

151690

Hom.:

11774

Cov.:

AF XY:

0.384

AC XY:

28479

AN XY:

74070

show subpopulations

African (AFR)

AF:

0.239

AC:

9905

AN:

41418

American (AMR)

AF:

0.497

AC:

7588

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.441

AC:

1530

AN:

3468

East Asian (EAS)

AF:

0.862

AC:

4366

AN:

5066

South Asian (SAS)

AF:

0.532

AC:

2561

AN:

4812

European-Finnish (FIN)

AF:

0.475

AC:

4993

AN:

10514

Middle Eastern (MID)

AF:

0.349

AC:

102

AN:

292

European-Non Finnish (NFE)

AF:

0.352

AC:

23895

AN:

67836

Other (OTH)

AF:

0.372

AC:

786

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1643

3286

4930

6573

8216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.378

Hom.:

25149

Bravo

AF:

0.370

TwinsUK

AF:

0.340

AC:

1260

ALSPAC

AF:

0.351

AC:

1353

ESP6500AA

AF:

0.223

AC:

929

ESP6500EA

AF:

0.331

AC:

2791

ExAC

AF:

0.327

AC:

36311

Asia WGS

AF:

0.645

AC:

2241

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency 5

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 23, 2016

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary dilated cardiomyopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;.;T;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.66

.;.;.;T;T;T

MetaRNN

Benign

0.000010

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

4.1

.;.;.;H;.;.

PhyloP100

2.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

N;N;N;N;.;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.019

D;D;T;T;.;T

Sift4G

Uncertain

0.015

D;D;D;D;D;D

Polyphen

0.99, 1.0

.;.;.;D;.;D

Vest4

0.33

MPC

0.75

ClinPred

0.094

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

Mutation Taster

=98/2

polymorphism (auto)

(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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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