NM_006073.4:c.1923_1924delAA
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_006073.4(TRDN):c.1923_1924delAA(p.Leu643SerfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006073.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151954Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000222 AC: 3AN: 135056Hom.: 0 AF XY: 0.0000280 AC XY: 2AN XY: 71556
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000740 AC: 9AN: 1216692Hom.: 0 AF XY: 0.00000497 AC XY: 3AN XY: 603672
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151954Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
This sequence change creates a premature translational stop signal (p.Leu643Serfs*19) in the TRDN gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with TRDN-related conditions. 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 c.1923_1924delAA variant, located in coding exon 37 of the TRDN gene, results from a deletion of two nucleotides at nucleotide positions 1923 to 1924, causing a translational frameshift with a predicted alternate stop codon (p.L643Sfs*19). This alteration has been reported in a sudden unexplained death cohort; however, clinical details were limited (Neubauer J et al. Int J Legal Med, 2021 Jul;135:1341-1349). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at