rs61736929

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006440.5(TXNRD2):c.526G>C(p.Glu176Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,614,186 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 124 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 128 hom. )

Consequence

TXNRD2
NM_006440.5 missense, splice_region

Scores

Splicing: ADA: 0.8753

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.59

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019516945).

BP6

Variant 22-19915767-C-G is Benign according to our data. Variant chr22-19915767-C-G is described in ClinVar as [Benign]. Clinvar id is 386317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.526G>C	p.Glu176Gln	missense_variant, splice_region_variant	6/18	ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.526G>C	p.Glu176Gln	missense_variant, splice_region_variant	6/18	1	NM_006440.5	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3323

AN:

152198

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0767

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00547

AC:

1364

AN:

249576

Hom.:

AF XY:

0.00416

AC XY:

563

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.0787

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00221

AC:

3230

AN:

1461870

Hom.:

128

Cov.:

AF XY:

0.00194

AC XY:

1410

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0809

Gnomad4 AMR exome

AF:

0.00391

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000647

Gnomad4 OTH exome

AF:

0.00407

GnomAD4 genome

AF:

0.0220

AC:

3348

AN:

152316

Hom.:

124

Cov.:

AF XY:

0.0208

AC XY:

1553

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0771

Gnomad4 AMR

AF:

0.00640

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.0245

ESP6500AA

AF:

0.0666

AC:

269

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.00655

AC:

792

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2016

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. -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

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

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

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

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.10

Sift

Benign

0.080

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

Sift4G

Benign

0.14

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

Polyphen

0.84, 0.91

.;.;.;.;P;.;P

Vest4

0.32

MVP

0.68

MPC

0.27

ClinPred

0.012

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.88

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.020

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