6-123366180-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006073.4(TRDN):c.1276A>C(p.Thr426Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,612,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006073.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRDN | NM_006073.4 | c.1276A>C | p.Thr426Pro | missense_variant, splice_region_variant | Exon 20 of 41 | ENST00000334268.9 | NP_006064.2 | |
TRDN | NM_001251987.2 | c.1279A>C | p.Thr427Pro | missense_variant, splice_region_variant | Exon 20 of 21 | NP_001238916.1 | ||
TRDN | NM_001407315.1 | c.1219A>C | p.Thr407Pro | missense_variant, splice_region_variant | Exon 19 of 20 | NP_001394244.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRDN | ENST00000334268.9 | c.1276A>C | p.Thr426Pro | missense_variant, splice_region_variant | Exon 20 of 41 | 1 | NM_006073.4 | ENSP00000333984.5 | ||
TRDN | ENST00000662930.1 | c.1279A>C | p.Thr427Pro | missense_variant, splice_region_variant | Exon 20 of 21 | ENSP00000499585.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248566Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134854
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1460664Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 726624
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 426 of the TRDN protein (p.Thr426Pro). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 532313). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
The p.T426P variant (also known as c.1276A>C), located in coding exon 20 of the TRDN gene, results from an A to C substitution at nucleotide position 1276. The threonine at codon 426 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at