chr22-19895506-C-G

Position:

chr22-19895506-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000400521.7(TXNRD2):c.850G>C(p.Val284Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TXNRD2
ENST00000400521.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.42

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13768476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.850G>C	p.Val284Leu	missense_variant	11/18	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.850G>C	p.Val284Leu	missense_variant	11/18	1	NM_006440.5	ENSP00000383365	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249066

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000677

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2020

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 240656; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31983221) -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 16, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TXNRD2 protein function. ClinVar contains an entry for this variant (Variation ID: 240656). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). This variant is present in population databases (rs201177571, gnomAD 0.005%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 284 of the TXNRD2 protein (p.Val284Leu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2022

The p.V284L variant (also known as c.850G>C), located in coding exon 11 of the TXNRD2 gene, results from a G to C substitution at nucleotide position 850. The valine at codon 284 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

.;T;.;.;T;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

.;.;.;.;L;.;.

MutationTaster

Benign

0.95

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

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.2

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

REVEL

Benign

0.099

Sift

Benign

0.22

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

Sift4G

Benign

0.20

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

Polyphen

0.032, 0.025

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

Vest4

0.17

MVP

0.41

MPC

0.21

ClinPred

0.12

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.096

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