rs45489199
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The ENST00000423572.7(SCN5A):āc.6013C>Gā(p.Pro2005Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,534,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2005R) has been classified as Uncertain significance.
Frequency
Genomes: š 0.0011 ( 0 hom., cov: 33)
Exomes š: 0.0012 ( 1 hom. )
Consequence
SCN5A
ENST00000423572.7 missense
ENST00000423572.7 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: -0.0910
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 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). GenCC has associacion of 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=0.010572314).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.6016C>G | p.Pro2006Ala | missense_variant | 28/28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.6013C>G | p.Pro2005Ala | missense_variant | 28/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.6016C>G | p.Pro2006Ala | missense_variant | 28/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
| SCN5A | ENST00000423572.7 | c.6013C>G | p.Pro2005Ala | missense_variant | 28/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes 0.00106 AC: 159AN: 149550Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00109 AC: 214AN: 195458Hom.: 1 AF XY: 0.00114 AC XY: 118AN XY: 103068
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GnomAD4 exome AF: 0.00125 AC: 1725AN: 1385136Hom.: 1 Cov.: 31 AF XY: 0.00122 AC XY: 826AN XY: 678678
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GnomAD4 genome 0.00106 AC: 159AN: 149670Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 75AN XY: 73196
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:16Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4Other:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2020 | This variant is associated with the following publications: (PMID: 22378279, 22360817, 21215473, 19597050, 26749013, 20875080, 2107088, 23714088, 27153395, 28988457, 10961955, 23631430, 23465283, 21070882, 17210839, 17210841, 15851227, 21410720, 21109022, 26159999, 23571586, 20129283, 29032884, 28831623, 28807990, 28798025, 16712702, 16379539, 19841300, 25351510, 26746457, 28301460, 29728395, 29672598, 30762279, 31337358, 31043699, 32880476) - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2020 | - - |
| 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:10961955;PMID:15851227;PMID:16379539;PMID:16712702;PMID:17210839;PMID:19841300;PMID:19597050;PMID:21109022;PMID:21410720;PMID:21070882;PMID:20129283). - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | SCN5A: BS2 - |
not specified Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2020 | Variant summary: SCN5A c.6016C>G (p.Pro2006Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 229592control chromosomes (gnomAD and publication data), including 1 homozygote. The observed variant frequency is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. The variant, c.6016C>G, has been reported in the literature in individuals affected with Long QT Syndrome and sudden death, but was also detected in controls (Aziz_2013, Christiansen_2014, Kapa_2009, Krahn_2009, Marcondes_2017). This variant has been reported not associate with any ECG characteristics in one large cohort, but associate with cardiac arrest and VF in another large cohort (Paludan-Muller_2019). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. Functional studies have shown the Pro2006Ala variant to exhibit increased persistent sodium currents in whole-cell voltage clamp measurements (Wang_2007, Shinlapawittayatorn_2011). Interestingly, when two variants, P2006A and a common polymorphism H558R, were expressed on the same allele, the cells displayed currents that behaved like wild type (Shinlapawittayatorn_2011). Therefore the biological significance of these in vitro studies is unclear. In fact, a case-control study showed that individuals with the variant of interest did not have significantly different QTc interval times compared to non-variant carriers (Ghouse_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 01, 2015 | p.Pro2006Ala in exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 0.2% (124/63230) of European chr omosomes and 0.23% (15/6614) of Finnish chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45489199). Additionally, proline (Pro) at position 2006 is not conserved in mammals or evolutionarily dis tant species and this variant has been identified in at least 5 mammals. Please note, this variant has been reported in the literature in 4 individuals with lon g QT, 5 individuals with VF, 2 cases of SIDS (Priori 2000, Ackerman 2004, Arnest ad 2007, Krahn 2009, Skinner 2011, Shinlapawittayatorn 2011, Novotny 2011). Stud ies have shown that the p.Pro2006Ala variant exhibits increased persistent sodiu m currents in whole-cell voltage clamp measurements (Wang 2007, Shinlapawittayat orn 2011), but behaves like wild type when expressed with the p.His558Arg varian t (Shinlapawittayatorn 2011). However, these in vitro assays may not accurately represent biological function. - |
| Likely benign, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 10, 2015 | - - |
Brugada syndrome 1 Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Nov 27, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Cardiac arrhythmia Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 25, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 28, 2018 | - - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). 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. - |
Long QT syndrome 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). 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. - |
Dilated cardiomyopathy 1E Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
SCN5A-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 08, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiomyopathy Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 02, 2021 | - - |
Sick sinus syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Progressive familial heart block, type 1A Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 23, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;.;.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;T;T;T;T;T;.;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;.;N;.;.;.
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;B;.;B;.;B;B;.;.
Vest4
MVP
MPC
0.50
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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