chr22-19877127-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006440.5(TXNRD2):​c.1553C>T​(p.Thr518Met) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,600,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T518T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

1
6
11

Clinical Significance

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

Conservation

PhyloP100: 5.08
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2811219).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TXNRD2NM_006440.5 linkuse as main transcriptc.1553C>T p.Thr518Met missense_variant 17/18 ENST00000400521.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TXNRD2ENST00000400521.7 linkuse as main transcriptc.1553C>T p.Thr518Met missense_variant 17/181 NM_006440.5 P4Q9NNW7-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152106
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000105
AC:
26
AN:
246632
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
134398
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:
0.0000468
Gnomad NFE exome
AF:
0.000224
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000137
AC:
198
AN:
1448514
Hom.:
0
Cov.:
31
AF XY:
0.000150
AC XY:
108
AN XY:
718192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000382
Gnomad4 NFE exome
AF:
0.000168
Gnomad4 OTH exome
AF:
0.000151
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000128
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000237
AC:
2
ExAC
AF:
0.0000992
AC:
12
EpiCase
AF:
0.000109
EpiControl
AF:
0.000238

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 submitterclinical testingGeneDxFeb 28, 2023Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 06, 2024This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 518 of the TXNRD2 protein (p.Thr518Met). This variant is present in population databases (rs372446673, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TXNRD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1775101). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 submitterclinical testingAmbry GeneticsJun 12, 2023The p.T518M variant (also known as c.1553C>T), located in coding exon 17 of the TXNRD2 gene, results from a C to T substitution at nucleotide position 1553. The threonine at codon 518 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
.;.;.;.;.;T;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
.;D;.;.;.;D;.
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.6
.;.;.;.;.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.3
D;.;.;D;D;D;.
REVEL
Benign
0.19
Sift
Benign
0.060
T;.;.;T;T;T;.
Sift4G
Benign
0.094
T;T;T;T;T;T;T
Polyphen
0.89
.;.;.;.;.;P;.
Vest4
0.61
MVP
0.74
MPC
0.23
ClinPred
0.18
T
GERP RS
4.3
Varity_R
0.15

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: rs372446673; hg19: chr22-19864650; COSMIC: COSV68692459; API