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rs1805124

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001099404.2(SCN5A):c.1673A>G(p.His558Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,720 control chromosomes in the GnomAD database, including 43,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H558Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 4753 hom., cov: 32)
Exomes 𝑓: 0.23 ( 39221 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

1
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:27O:1

Conservation

PhyloP100: 1.28
Variant links:
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 -19 ACMG points.

PP2
Missense variant where missense usually causes diseases, SCN5A
BP4
Computational evidence support a benign effect (MetaRNN=0.002580464).
BP6
Variant 3-38603929-T-C is Benign according to our data. Variant chr3-38603929-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603929-T-C is described in Lovd as [Benign]. Variant chr3-38603929-T-C is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.1673A>G p.His558Arg missense_variant 12/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.1673A>G p.His558Arg missense_variant 12/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.1673A>G p.His558Arg missense_variant 12/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.1673A>G p.His558Arg missense_variant 12/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.245
AC:
37263
AN:
151978
Hom.:
4732
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.293
Gnomad AMI
AF:
0.339
Gnomad AMR
AF:
0.230
Gnomad ASJ
AF:
0.188
Gnomad EAS
AF:
0.101
Gnomad SAS
AF:
0.241
Gnomad FIN
AF:
0.197
Gnomad MID
AF:
0.222
Gnomad NFE
AF:
0.240
Gnomad OTH
AF:
0.239
GnomAD3 exomes
AF:
0.220
AC:
54882
AN:
249044
Hom.:
6383
AF XY:
0.223
AC XY:
30153
AN XY:
135142
show subpopulations
Gnomad AFR exome
AF:
0.292
Gnomad AMR exome
AF:
0.216
Gnomad ASJ exome
AF:
0.201
Gnomad EAS exome
AF:
0.0933
Gnomad SAS exome
AF:
0.247
Gnomad FIN exome
AF:
0.200
Gnomad NFE exome
AF:
0.230
Gnomad OTH exome
AF:
0.228
GnomAD4 exome
AF:
0.230
AC:
335541
AN:
1461624
Hom.:
39221
Cov.:
35
AF XY:
0.231
AC XY:
167767
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.294
Gnomad4 AMR exome
AF:
0.219
Gnomad4 ASJ exome
AF:
0.197
Gnomad4 EAS exome
AF:
0.0938
Gnomad4 SAS exome
AF:
0.240
Gnomad4 FIN exome
AF:
0.199
Gnomad4 NFE exome
AF:
0.234
Gnomad4 OTH exome
AF:
0.233
GnomAD4 genome
AF:
0.246
AC:
37344
AN:
152096
Hom.:
4753
Cov.:
32
AF XY:
0.245
AC XY:
18242
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.294
Gnomad4 AMR
AF:
0.230
Gnomad4 ASJ
AF:
0.188
Gnomad4 EAS
AF:
0.101
Gnomad4 SAS
AF:
0.242
Gnomad4 FIN
AF:
0.197
Gnomad4 NFE
AF:
0.240
Gnomad4 OTH
AF:
0.241
Alfa
AF:
0.235
Hom.:
10325
Bravo
AF:
0.249
TwinsUK
AF:
0.234
AC:
869
ALSPAC
AF:
0.230
AC:
885
ESP6500AA
AF:
0.275
AC:
1151
ESP6500EA
AF:
0.232
AC:
1957
ExAC
AF:
0.221
AC:
26760
Asia WGS
AF:
0.202
AC:
702
AN:
3478
EpiCase
AF:
0.246
EpiControl
AF:
0.234

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:27Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 22, 2014- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteMar 05, 2020- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 09, 201227% (1151/5339) of Afr Amer chrom in ESP -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Pathogenic:1Benign:5Other:1
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncApr 20, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 22, 2020Observed in 62556/280350 alleles (22.31%), including 7355 homozygous individuals, in large population cohorts, suggesting the variant is benign (Lek et al., 2016); Reported in ClinVar as likely benign or benign (ClinVar Variant ID# 48289; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16864729, 26606670, 24332189, 30968627, 26084969, 27554632, 29202755, 27381756, 18368697, 26846766, 27153395, 12569159, 21216356, 21076409, 18803136, 19549036, 20384651, 24388587, 15599693, 22370996, 22064211, 15992732, 21109022, 15851227, 20129283, 25177937, 17185997, 24762593, 14500339, 21840964, 24951663, 21705349, 31043699) -
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported in the following publications (PMID:10807545;PMID:11463728;PMID:11997281;PMID:12569159;PMID:12639704;PMID:14760488;PMID:14985827;PMID:15161528;PMID:15599693;PMID:15689442;PMID:16132053;PMID:16155735;PMID:16239976;PMID:16712702;PMID:17161064;PMID:17210839;PMID:17675083;PMID:17993325;PMID:18093912;PMID:18156160;PMID:18362431;PMID:18426444;PMID:19083750;PMID:19841300;PMID:20129283). -
Pathogenic, no assertion criteria providedresearchBiology Molecular and Stem Cell Facilities Laboratory, National Cardiovascular Center, Harapan Kita Hospital-Allele Freq Eas (0.1012); Sift: tolerated (1); PolyPhen: benign (0) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversityJul 18, 2011- -
Brugada syndrome 1 Benign:3
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Dilated cardiomyopathy 1E Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Ventricular fibrillation, paroxysmal familial, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
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 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 28, 2022- -
Sick sinus syndrome 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Congenital long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Progressive familial heart block, type 1A Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Primary dilated cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCohesion PhenomicsSep 27, 2022- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2015This alteration is classified as benign based on a combination of the following: 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 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Cardiac arrhythmia Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 15, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.22
Cadd
Benign
1.1
Dann
Benign
0.29
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.024
N
MetaRNN
Benign
0.0026
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
P;P;P;P;P;P;P;P;P;P
PrimateAI
Benign
0.30
T
PROVEAN
Benign
3.9
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.29
Sift
Benign
1.0
T;T;T;T;T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;.;B;B;.;.
Vest4
0.029
MPC
0.42
ClinPred
0.0038
T
GERP RS
2.4
Varity_R
0.032
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1805124; hg19: chr3-38645420; COSMIC: COSV61125544; API