rs372271677
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong
The NM_001099404.2(SCN5A):c.2268C>T(p.Phe756=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000867 in 1,613,880 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 synonymous
NM_001099404.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.22
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 Benign. Variant got -8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 3-38587568-G-A is Benign according to our data. Variant chr3-38587568-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38587568-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2268C>T | p.Phe756= | synonymous_variant | 15/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.2268C>T | p.Phe756= | synonymous_variant | 15/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2268C>T | p.Phe756= | synonymous_variant | 15/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.2268C>T | p.Phe756= | synonymous_variant | 15/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249206Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135190
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461656Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727114
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74370
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Phe756Phe in exon 15 of SCN5A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1/3380 African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2018 | 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2023 | 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
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 24, 2019 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at