rs144511230
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000335.5(SCN5A):c.1441C>T(p.Arg481Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,613,928 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0034 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 5 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 3.33
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 -12 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ: 2.7504 (greater than the threshold 3.09). Trascript score misZ: 4.8279 (greater than threshold 3.09). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.007048309).
BP6
Variant 3-38604806-G-A is Benign according to our data. Variant chr3-38604806-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48284.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, not_provided=1, Benign=12}. Variant chr3-38604806-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00342 (521/152276) while in subpopulation AFR AF= 0.0118 (492/41554). AF 95% confidence interval is 0.011. There are 4 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 SD gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1441C>T | p.Arg481Trp | missense_variant | 11/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.1441C>T | p.Arg481Trp | missense_variant | 11/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.00340 AC: 517AN: 152158Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.000867 AC: 216AN: 249156Hom.: 2 AF XY: 0.000747 AC XY: 101AN XY: 135160
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GnomAD4 exome AF: 0.000398 AC: 582AN: 1461652Hom.: 5 Cov.: 31 AF XY: 0.000366 AC XY: 266AN XY: 727108
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GnomAD4 genome AF: 0.00342 AC: 521AN: 152276Hom.: 4 Cov.: 32 AF XY: 0.00357 AC XY: 266AN XY: 74462
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ESP6500AA
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:18Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | Arg481Trp in exon 11 of SCN5A: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (29/3250) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs144511230). Arg481Trp in exon 11 of SCN5A ( rs144511230; allele frequency = 0.9%, 29/3250) ** - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 23, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:4Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19841300;PMID:20129283). - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2025 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | SCN5A: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 29874177, 15992732) - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 30, 2022 | - - |
Cardiac arrhythmia Benign:2
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 20, 2018 | - - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Progressive familial heart block, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Brugada syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Brugada syndrome;C1859062:Long QT syndrome 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 30, 2015 | - - |
Dilated cardiomyopathy 1E Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Sick sinus syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Long QT syndrome 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2015 | This alteration is classified as 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. - |
Long QT syndrome 3;C4551804:Brugada syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 21, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
B;D;.;B;.;B;D;.;.
Vest4
MVP
MPC
0.92
ClinPred
T
GERP RS
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Splicing
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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