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rs45489199

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001099404.2(SCN5A):c.6016C>G(p.Pro2006Ala) 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. P2006R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

1
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:15O:1

Conservation

PhyloP100: -0.0910
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 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=0.010572314).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.6016C>G p.Pro2006Ala missense_variant 28/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.6013C>G p.Pro2005Ala missense_variant 28/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.6016C>G p.Pro2006Ala missense_variant 28/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.6013C>G p.Pro2005Ala missense_variant 28/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00106
AC:
159
AN:
149550
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000222
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000199
Gnomad ASJ
AF:
0.000292
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00228
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00182
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00109
AC:
214
AN:
195458
Hom.:
1
AF XY:
0.00114
AC XY:
118
AN XY:
103068
show subpopulations
Gnomad AFR exome
AF:
0.000201
Gnomad AMR exome
AF:
0.000110
Gnomad ASJ exome
AF:
0.000411
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000111
Gnomad FIN exome
AF:
0.00139
Gnomad NFE exome
AF:
0.00192
Gnomad OTH exome
AF:
0.000881
GnomAD4 exome
AF:
0.00125
AC:
1725
AN:
1385136
Hom.:
1
Cov.:
31
AF XY:
0.00122
AC XY:
826
AN XY:
678678
show subpopulations
Gnomad4 AFR exome
AF:
0.000127
Gnomad4 AMR exome
AF:
0.000247
Gnomad4 ASJ exome
AF:
0.000189
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000949
Gnomad4 FIN exome
AF:
0.00125
Gnomad4 NFE exome
AF:
0.00148
Gnomad4 OTH exome
AF:
0.000808
GnomAD4 genome
AF:
0.00106
AC:
159
AN:
149670
Hom.:
0
Cov.:
33
AF XY:
0.00102
AC XY:
75
AN XY:
73196
show subpopulations
Gnomad4 AFR
AF:
0.000221
Gnomad4 AMR
AF:
0.000199
Gnomad4 ASJ
AF:
0.000292
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00228
Gnomad4 NFE
AF:
0.00182
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00141
Hom.:
0
Bravo
AF:
0.000846
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000249
AC:
1
ESP6500EA
AF:
0.00155
AC:
13
ExAC
AF:
0.00123
AC:
146

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:15Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4Other:1
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 20, 2020- -
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: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 submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024SCN5A: BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 05, 2020This 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 submitterclinical testingInvitaeJan 31, 2024- -
not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 07, 2020Variant 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 01, 2015p.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 submitterclinical testingBlueprint GeneticsNov 10, 2015- -
Brugada syndrome 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesNov 27, 2017- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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. -
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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. -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 02, 2021- -
SCN5A-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 08, 2020This 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). -
Sick sinus syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMar 23, 2018This 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 submitterclinical testingAmbry GeneticsOct 26, 2018This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 28, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.17
Cadd
Benign
2.0
Dann
Benign
0.35
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.11
N
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.011
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.36
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.0
N;N;N;N;N;N;N;N;N
REVEL
Benign
0.28
Sift
Benign
0.60
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.80
T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;.;B;B;.;.
Vest4
0.13
MVP
0.69
MPC
0.50
ClinPred
0.0037
T
GERP RS
-2.6
Varity_R
0.039
gMVP
0.43

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: rs45489199; hg19: chr3-38591847; API