rs201041981
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_006073.4(TRDN):c.2179C>T(p.Gln727Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,611,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
TRDN
NM_006073.4 stop_gained
NM_006073.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.76
Genes affected
TRDN (HGNC:12261): (triadin) This gene encodes an integral membrane protein found in skeletal and cardiac muscle. The encoded protein plays a role in skeletal muscle excitation-contraction coupling as part of the calcium release complex and is required for normal skeletal muscle strength. This protein indirectly links triads and microtubules in skeletal muscle. Mutations in this gene are associated with cardiac arrythmia syndrome and some variants in this gene may be associated with sudden cardiac death. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00502 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRDN | NM_006073.4 | c.2179C>T | p.Gln727Ter | stop_gained | 41/41 | ENST00000334268.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRDN | ENST00000334268.9 | c.2179C>T | p.Gln727Ter | stop_gained | 41/41 | 1 | NM_006073.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151902Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000445 AC: 11AN: 247372Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134210
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GnomAD4 exome AF: 0.0000500 AC: 73AN: 1459464Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 31AN XY: 726036
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 151902Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74156
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 13, 2023 | PVS1_moderate - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | This sequence change creates a premature translational stop signal (p.Gln727*) in the TRDN gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs201041981, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 566685). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 | Oct 05, 2021 | The p.Q727* variant (also known as c.2179C>T), located in coding exon 41 of the TRDN gene, results from a C to T substitution at nucleotide position 2179. This changes the amino acid from a glutamine to a stop codon within coding exon 41. This alteration occurs at the 3' terminus of theTRDN gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last three amino acids of the protein. The exact functional effect of this alteration is unknown. Furthermore, this alteration does not impact the predominant cardiac isoform of TRDN (NM_001256021.1; Kobayashi YM et al. J. Biol. Chem., 1999 Oct;274:28660-8). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
N;N
Vest4
GERP RS
Splicing
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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