3-38580942-ACTC-A
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_001099404.2(SCN5A):βc.3214_3216delβ(p.Glu1072del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000483 in 1,448,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000048 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 inframe_deletion
NM_001099404.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.01
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_001099404.2
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001099404.2. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.3214_3216del | p.Glu1072del | inframe_deletion | 17/28 | ENST00000423572.7 | NP_000326.2 | |
SCN5A | NM_001099404.2 | c.3214_3216del | p.Glu1072del | inframe_deletion | 17/28 | ENST00000413689.6 | NP_001092874.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3214_3216del | p.Glu1072del | inframe_deletion | 17/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
SCN5A | ENST00000423572.7 | c.3214_3216del | p.Glu1072del | inframe_deletion | 17/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244388Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132364
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GnomAD4 exome AF: 0.00000483 AC: 7AN: 1448272Hom.: 0 AF XY: 0.00000557 AC XY: 4AN XY: 717690
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 18, 2023 | This variant, c.3214_3216del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Glu1072del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758282196, gnomAD 0.007%). 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: 532071). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2020 | Variant summary: SCN5A c.3214_3216delGAG (p.Glu1072del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 244388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3214_3216delGAG in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2023 | The c.3214_3216delGAG variant (also known as p.E1072del) is located in coding exon 16 of the SCN5A gene. This variant results from an in-frame GAG deletion at nucleotide positions 3214 to 3216. This results in the in-frame deletion of a glutamic acid at codon 1072, and is located in the interdomain linker DII/DIII region. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 30, 2023 | This variant causes a deletion of glutamate at codon 1072 of the SCN5A protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (doi:10.1016/j.cardfail.2022.03.310). This variant has been identified in 3/244388 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. - |
Computational scores
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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