rs5748469

Positions:

chr22-19919576-C-A

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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=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 id 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/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.196G>T	p.Ala66Ser	missense_variant	3/18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.196G>T	p.Ala66Ser	missense_variant	3/18	1	NM_006440.5	ENSP00000383365	P4	Q9NNW7-1

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

GnomAD3 exomes

AF:

0.449

AC:

77201

AN:

172046

Hom.:

19688

AF XY:

0.442

AC XY:

40596

AN XY:

91746

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 SAS exome

AF:

0.505

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

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.597

Gnomad4 ASJ exome

AF:

0.424

Gnomad4 EAS exome

AF:

0.853

Gnomad4 SAS exome

AF:

0.508

Gnomad4 FIN exome

AF:

0.468

Gnomad4 NFE exome

AF:

0.352

Gnomad4 OTH exome

AF:

0.407

GnomAD4 genome

AF:

0.370

AC:

56120

AN:

151690

Hom.:

11774

Cov.:

AF XY:

0.384

AC XY:

28479

AN XY:

74070

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.497

Gnomad4 ASJ

AF:

0.441

Gnomad4 EAS

AF:

0.862

Gnomad4 SAS

AF:

0.532

Gnomad4 FIN

AF:

0.475

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.372

Alfa

AF:

0.377

Hom.:

16722

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

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;.;.

MutationTaster

Benign

0.000019

P;P;P;P;P;P;P

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

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