22-19880654-C-T

Position:

chr22-19880654-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006440.5(TXNRD2):c.1150G>A(p.Gly384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 1,613,390 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G384R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 79 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.33

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055096447).

BP6

Variant 22-19880654-C-T is Benign according to our data. Variant chr22-19880654-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19880654-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.1150G>A	p.Gly384Ser	missense_variant	13/18	ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.1150G>A	p.Gly384Ser	missense_variant	13/18	1	NM_006440.5	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1073

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00795

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00760

AC:

1891

AN:

248654

Hom.:

AF XY:

0.00709

AC XY:

959

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.000390

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.0381

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.00845

GnomAD4 exome

AF:

0.00610

AC:

8906

AN:

1461064

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

4352

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.0425

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.0185

Gnomad4 NFE exome

AF:

0.00560

Gnomad4 OTH exome

AF:

0.00689

GnomAD4 genome

AF:

0.00704

AC:

1073

AN:

152326

Hom.:

Cov.:

AF XY:

0.00749

AC XY:

558

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00686

Gnomad4 ASJ

AF:

0.0444

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0205

Gnomad4 NFE

AF:

0.00795

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00786

Hom.:

Bravo

AF:

0.00547

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000724

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00764

AC:

924

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TXNRD2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2017

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

May 15, 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

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.33

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

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

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

MetaRNN

Benign

0.0055

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.18

Sift

Benign

0.12

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

Sift4G

Benign

0.17

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

Polyphen

0.37

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

Vest4

0.34

MVP

0.56

MPC

0.21

ClinPred

0.014

GERP RS

4.3

Varity_R

0.080

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