rs41311127
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_001099404.2(SCN5A):c.3878T>C(p.Phe1293Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000345 in 1,613,890 control chromosomes in the GnomAD database, including 1 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 0.00046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00033 ( 1 hom. )
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 4.44
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 Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SCN5A
BP4
?
Computational evidence support a benign effect (MetaRNN=0.05141446).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3878T>C | p.Phe1293Ser | missense_variant | 22/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3875T>C | p.Phe1292Ser | missense_variant | 22/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3878T>C | p.Phe1293Ser | missense_variant | 22/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3875T>C | p.Phe1292Ser | missense_variant | 22/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000460 AC: 70AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000648 AC: 161AN: 248636Hom.: 0 AF XY: 0.000660 AC XY: 89AN XY: 134920
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GnomAD4 exome AF: 0.000333 AC: 486AN: 1461568Hom.: 1 Cov.: 31 AF XY: 0.000345 AC XY: 251AN XY: 727062
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GnomAD4 genome ? AF: 0.000460 AC: 70AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:5Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2017 | Variant summary: The SCN5A c.3878T>C (p.Phe1293Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 49/119844 control chromosomes including ExAC at a frequency of 0.0004089, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667), suggesting this variant is likely a benign polymorphism. This variant has been reported in two Brugada syndrome (BrS) patients and one patient presenting with sodium channelopathy (cardiac symptoms, positive family history, and/or abnormal electrocardiogram) in literature (Priori_2002, Chockalingam_2012, and Sommariva_2013). In one BrS patient, another truncating variant c.3258-3261del4 (p.E1087PfsX57) was also present (Sommariva_2013), supporting benign outcome. It has been also reported as polymorphism from published sources (Kapa_2009, Kapplinger_2010) as it was found in healthy controls of European origin. In ClinVar while two clinical labs have classified this variant as VUS, one lab has classified as likely benign. Taken together, this variant is currently classified as likely benign. - |
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:11901046;PMID:15851227;PMID:19841300;PMID:20129283). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 33083721, 30847666, 29167113, 27153395, 11901046, 22885917, 15851227, 20129283, 23414114) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | SCN5A: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 01, 2019 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 17, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 23, 2014 | The Phe1293Ser variant in SCN5A has been reported in 2 individuals with Brugada syndrome (Priori 2002, Sommariva 2012), one of whom carried a frameshift variant in the other copy of SCN5A, but has also been identified in 1/590 Caucasian con trol chromosomes (Ackerman 2004) and in 4/8412 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/; dbSNP rs41311 127). This variant has also been identified by our laboratory in 1 Caucasian ind ividual with DCM, who had a pathogenic variant in a different gene. The affected amino acid is poorly conserved in evolution, raising the possibility that a cha nge at this position would be tolerated. Other computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Phe1293Ser variant is uncertain. - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | SCN5A NM_198056.3 exon 22 p.Phe1293Ser (c.3878T>C): This variant has been reported in the literature in at least two individuals with Brugada syndrome, one of whom also carried a truncating variant in SCN5A (Priori 2002 PMID:11901046, Sommariva 2012). However, this variant is present in 0.9% (93/10336) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-38603991-A-G) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:67833). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Long QT syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of Long QT syndrome. - |
Brugada syndrome Benign:1
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2018 | 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 | Dec 17, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostArm
Benign
CardioboostCm
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
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
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;B;.;B;.;P;P;.;.
Vest4
MVP
MPC
1.9
ClinPred
T
GERP RS
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gMVP
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Name
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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