Genetic Variant TXNRD2:p.Leu367Leu (chr22-19880705-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006440.5(TXNRD2):c.1099C>T(p.Leu367Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,612,016 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 40 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 55 hom. )

Consequence

TXNRD2
NM_006440.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.16

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 22-19880705-G-A is Benign according to our data. Variant chr22-19880705-G-A is described in ClinVar as Benign. ClinVar VariationId is 263358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2235/151290) while in subpopulation AFR AF = 0.043 (1758/40864). AF 95% confidence interval is 0.0413. There are 40 homozygotes in GnomAd4. There are 1049 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006440.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TXNRD2	NM_006440.5	MANE Select	c.1099C>T	p.Leu367Leu	synonymous	Exon 13 of 18	NP_006431.2
TXNRD2	NM_001352300.2		c.1096C>T	p.Leu366Leu	synonymous	Exon 13 of 17	NP_001339229.1
TXNRD2	NM_001352301.2		c.1009C>T	p.Leu337Leu	synonymous	Exon 13 of 18	NP_001339230.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.1099C>T	p.Leu367Leu	synonymous	Exon 13 of 18	ENSP00000383365.1
TXNRD2	ENST00000400519.6	TSL:1	c.1096C>T	p.Leu366Leu	synonymous	Exon 13 of 17	ENSP00000383363.1
TXNRD2	ENST00000400518.5	TSL:1	c.1009C>T	p.Leu337Leu	synonymous	Exon 13 of 18	ENSP00000383362.1

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2231

AN:

151176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0139

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.00321

Gnomad OTH

AF:

0.0159

GnomAD2 exomes

AF:

0.00660

AC:

1635

AN:

247832

AF XY:

0.00595

show subpopulations

Gnomad AFR exome

AF:

0.0470

Gnomad AMR exome

AF:

0.00670

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00401

Gnomad OTH exome

AF:

0.00748

GnomAD4 exome

AF:

0.00410

AC:

5993

AN:

1460726

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

2827

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.0476

AC:

1593

AN:

33470

American (AMR)

AF:

0.00734

AC:

328

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

425

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000858

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000726

AC:

AN:

52376

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00269

AC:

2987

AN:

1111954

Other (OTH)

AF:

0.00754

AC:

455

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

286

573

859

1146

1432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.0148

AC:

2235

AN:

151290

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1049

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.0430

AC:

1758

AN:

40864

American (AMR)

AF:

0.0111

AC:

169

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00321

AC:

218

AN:

67860

Other (OTH)

AF:

0.0158

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

113

225

338

450

563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00947

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 11, 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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Aug 21, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

2.2

PromoterAI

-0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over