rs59935057
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_006073.4(TRDN):c.1871-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,264,438 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0083 ( 27 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 79 hom. )
Consequence
TRDN
NM_006073.4 splice_polypyrimidine_tract, intron
NM_006073.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.187
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.99).
BP6
?
Variant 6-123255917-C-T is Benign according to our data. Variant chr6-123255917-C-T is described in ClinVar as [Benign]. Clinvar id is 227117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123255917-C-T is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRDN | NM_006073.4 | c.1871-15G>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000334268.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRDN | ENST00000334268.9 | c.1871-15G>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_006073.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00822 AC: 1249AN: 151970Hom.: 24 Cov.: 32
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GnomAD3 exomes AF: 0.00266 AC: 146AN: 54960Hom.: 1 AF XY: 0.00272 AC XY: 81AN XY: 29726
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GnomAD4 exome AF: 0.00250 AC: 2786AN: 1112352Hom.: 79 Cov.: 20 AF XY: 0.00245 AC XY: 1323AN XY: 539638
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GnomAD4 genome ? AF: 0.00834 AC: 1268AN: 152086Hom.: 27 Cov.: 32 AF XY: 0.00893 AC XY: 664AN XY: 74332
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2023 | Variant summary: TRDN c.1871-15G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. The variant allele was found at a frequency of 0.0027 in 54960 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRDN causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1871-15G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | 1871-15G>A in intron 35 of TRDN: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (42/3350) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs59935057). - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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