rs187531872
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000335.5(SCN5A):c.998+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000103 in 1,595,662 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000335.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.998+5G>A | splice_region_variant, intron_variant | Intron 8 of 27 | ENST00000413689.6 | NP_001092874.1 | ||
SCN5A | NM_000335.5 | c.998+5G>A | splice_region_variant, intron_variant | Intron 8 of 27 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.998+5G>A | splice_region_variant, intron_variant | Intron 8 of 27 | 5 | NM_001099404.2 | ENSP00000410257.1 | |||
SCN5A | ENST00000423572.7 | c.998+5G>A | splice_region_variant, intron_variant | Intron 8 of 27 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000189 AC: 47AN: 249120Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135142
GnomAD4 exome AF: 0.0000963 AC: 139AN: 1443472Hom.: 0 Cov.: 27 AF XY: 0.000110 AC XY: 79AN XY: 719484
GnomAD4 genome AF: 0.000171 AC: 26AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74354
ClinVar
Submissions by phenotype
not specified Uncertain:1
The 998+5G>A variant in SCN5A has not been reported in individuals with cardiomyopathy, but it has been identified in 1/8366 of European American chromosomes by the NHLBI Exome Sequencing Project and in 0.5% (1/186) of Finnish chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/;dbSNP rs187531872). This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the 998+5G>A variant. 998+5G>A intron 8 of SCN5A (rs187531872; allele frequency = 1/8366). This variant has been seen by several clinical labs in ClinVar (uncertain significance), and affects splice in silico. This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
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Primary dilated cardiomyopathy Uncertain:1
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not provided Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Cardiac arrhythmia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at