rs201672269
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001099404.2(SCN5A):c.934+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000325 in 1,600,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001099404.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.934+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000423572.7 | |||
SCN5A | NM_001099404.2 | c.934+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.934+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_001099404.2 | P4 | |||
SCN5A | ENST00000423572.7 | c.934+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000648 AC: 16AN: 247064Hom.: 0 AF XY: 0.0000746 AC XY: 10AN XY: 133994
GnomAD4 exome AF: 0.0000331 AC: 48AN: 1447990Hom.: 0 Cov.: 31 AF XY: 0.0000418 AC XY: 30AN XY: 717812
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74474
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2023 | This variant causes a G>A nucleotide substitution at the +5 position of intron 7 of the SCN5A gene. Splice site prediction tools suggest that this variant may impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 16/247064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2023 | This variant causes a G>A nucleotide substitution at the +5 position of intron 7 of the SCN5A gene. Splice site prediction tools suggest that this variant may impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 16/247064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | This sequence change falls in intron 7 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 (rs201672269, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. 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: 580982). 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 may create or strengthen a splice site. 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 | Mar 19, 2024 | The c.934+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 6 in the SCN5A gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at