rs949932623
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The ENST00000423572.7(SCN5A):c.3388-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,607,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000423572.7 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.3388-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000423572.7 | NP_000326.2 | |||
SCN5A | NM_001099404.2 | c.3391-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000413689.6 | NP_001092874.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3391-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |||
SCN5A | ENST00000423572.7 | c.3388-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000419 AC: 1AN: 238510Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129220
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1455552Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2AN XY: 723214
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change falls in intron 18 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 378545). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 | Nov 16, 2023 | The c.3391-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 18 in the SCN5A gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2015 | 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. - |
Brugada syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | in vitro;research | Roden Lab, Vanderbilt University Medical Center | - | We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38576784-A-G was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000131 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as LB using these collective data. - |
Cardiac arrhythmia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at