chr22-19919551-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001352302.2(TXNRD2):c.-68C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,561,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 27)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
TXNRD2
NM_001352302.2 5_prime_UTR_premature_start_codon_gain
NM_001352302.2 5_prime_UTR_premature_start_codon_gain
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 9.08
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TXNRD2 | NM_006440.5 | c.221C>G | p.Ser74Cys | missense_variant | 3/18 | ENST00000400521.7 | NP_006431.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TXNRD2 | ENST00000400521.7 | c.221C>G | p.Ser74Cys | missense_variant | 3/18 | 1 | NM_006440.5 | ENSP00000383365.1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152048Hom.: 0 Cov.: 27
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GnomAD3 exomes AF: 0.000141 AC: 24AN: 170478Hom.: 0 AF XY: 0.000132 AC XY: 12AN XY: 90960
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GnomAD4 exome AF: 0.000237 AC: 334AN: 1409320Hom.: 0 Cov.: 30 AF XY: 0.000230 AC XY: 160AN XY: 696402
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152048Hom.: 0 Cov.: 27 AF XY: 0.0000808 AC XY: 6AN XY: 74244
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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 | Apr 30, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the TXNRD2 protein (p.Ser74Cys). This variant is present in population databases (rs200942544, gnomAD 0.02%). 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: 454284). 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 disruptive. 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 | Jun 05, 2023 | The p.S74C variant (also known as c.221C>G), located in coding exon 3 of the TXNRD2 gene, results from a C to G substitution at nucleotide position 221. The serine at codon 74 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;.;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;.;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;.;D
Vest4
MVP
MPC
0.78
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at