rs5992495

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006440.5(TXNRD2):​c.895A>T​(p.Ser299Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.036343426).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TXNRD2NM_006440.5 linkuse as main transcriptc.895A>T p.Ser299Cys missense_variant 11/18 ENST00000400521.7 NP_006431.2 Q9NNW7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TXNRD2ENST00000400521.7 linkuse as main transcriptc.895A>T p.Ser299Cys missense_variant 11/181 NM_006440.5 ENSP00000383365.1 Q9NNW7-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152116
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
249058
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135156
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461624
Hom.:
0
Cov.:
35
AF XY:
0.00000275
AC XY:
2
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152116
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 23, 2020The p.S299C variant (also known as c.895A>T), located in coding exon 11 of the TXNRD2 gene, results from an A to T substitution at nucleotide position 895. The serine at codon 299 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species, and cysteine 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
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
0.049
DANN
Benign
0.53
DEOGEN2
Benign
0.077
.;.;.;.;T;T;.
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.023
.;T;.;.;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.036
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.46
.;.;.;.;N;.;.
MutationTaster
Benign
1.0
P;P;P;P;P;P;P
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-1.3
N;.;N;N;N;.;N
REVEL
Benign
0.030
Sift
Benign
0.11
T;.;T;T;T;.;T
Sift4G
Uncertain
0.052
T;T;T;T;T;T;T
Polyphen
0.72, 0.0010
.;.;.;.;P;.;B
Vest4
0.097
MutPred
0.35
.;.;.;.;Loss of disorder (P = 0.0153);.;Loss of disorder (P = 0.0153);
MVP
0.14
MPC
0.20
ClinPred
0.082
T
GERP RS
-2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.095

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.

Other links and lift over

dbSNP: rs5992495; hg19: chr22-19882984; API