rs1057520531
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001099404.2(SCN5A):c.4437+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,431,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001099404.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.4434+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000423572.7 | |||
SCN5A | NM_001099404.2 | c.4437+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000413689.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4437+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_001099404.2 | P4 | |||
SCN5A | ENST00000423572.7 | c.4434+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000349 AC: 5AN: 1431962Hom.: 0 Cov.: 36 AF XY: 0.00000564 AC XY: 4AN XY: 709088
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Brugada syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 11, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | in vitro;research | Roden Lab, Vanderbilt University Medical Center | Oct 05, 2022 | The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change falls in intron 25 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2022 | The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Long QT syndrome 3 Uncertain:1
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Aug 23, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at