22-19895461-T-G

Position:

chr22-19895461-T-G

Variant summary

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

The NM_006440.5(TXNRD2):c.895A>C(p.Ser299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,808 control chromosomes in the GnomAD database, including 32,633 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 Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 7146 hom., cov: 33)

Exomes 𝑓: 0.17 ( 25487 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.812

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:

TXNRD2 (HGNC:):

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=1.9919422E-5).

BP6

Variant 22-19895461-T-G is Benign according to our data. Variant chr22-19895461-T-G is described in ClinVar as [Benign]. Clinvar id is 263411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.895A>C	p.Ser299Arg	missense_variant	11/18	ENST00000400521.7	NP_006431.2	Q9NNW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.895A>C	p.Ser299Arg	missense_variant	11/18	1	NM_006440.5	ENSP00000383365.1		Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39354

AN:

152086

Hom.:

7117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.0586

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.235

GnomAD3 exomes

AF:

0.179

AC:

44564

AN:

249058

Hom.:

5219

AF XY:

0.178

AC XY:

24054

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.521

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.0633

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.175

AC:

255419

AN:

1461604

Hom.:

25487

Cov.:

AF XY:

0.175

AC XY:

127304

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.538

Gnomad4 AMR exome

AF:

0.146

Gnomad4 ASJ exome

AF:

0.193

Gnomad4 EAS exome

AF:

0.0514

Gnomad4 SAS exome

AF:

0.201

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.183

GnomAD4 genome

AF:

0.259

AC:

39452

AN:

152204

Hom.:

7146

Cov.:

AF XY:

0.253

AC XY:

18856

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.511

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.177

Gnomad4 EAS

AF:

0.0587

Gnomad4 SAS

AF:

0.200

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.169

Gnomad4 OTH

AF:

0.236

Alfa

AF:

0.176

Hom.:

6094

Bravo

AF:

0.275

TwinsUK

AF:

0.177

AC:

657

ALSPAC

AF:

0.167

AC:

644

ESP6500AA

AF:

0.477

AC:

2062

ESP6500EA

AF:

0.166

AC:

1415

ExAC

AF:

0.188

AC:

22763

Asia WGS

AF:

0.155

AC:

538

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.179

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.0080

DANN

Benign

0.25

DEOGEN2

Benign

0.047

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

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.018

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

MetaRNN

Benign

0.000020

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.23

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.66

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

REVEL

Benign

0.015

Sift

Benign

0.42

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

Sift4G

Benign

0.49

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

Polyphen

0.0

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

Vest4

0.050

MutPred

0.31

.;.;.;.;Loss of glycosylation at S299 (P = 0.0237);.;Loss of glycosylation at S299 (P = 0.0237);

MPC

0.23

ClinPred

0.00026

GERP RS

-2.8

Varity_R

0.056

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