rs45488304
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2PP2BP4_StrongBP6_Very_Strong
The NM_001099404.2(SCN5A):c.1852C>T(p.Leu618Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,535,352 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 1 hom. )
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
3
6
8
Clinical Significance
Conservation
PhyloP100: 6.57
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 -9 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=0.010162026).
BP6
?
Variant 3-38603750-G-A is Benign according to our data. Variant chr3-38603750-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 67692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603750-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1852C>T | p.Leu618Phe | missense_variant | 12/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1852C>T | p.Leu618Phe | missense_variant | 12/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1852C>T | p.Leu618Phe | missense_variant | 12/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1852C>T | p.Leu618Phe | missense_variant | 12/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00163 AC: 248AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000478 AC: 92AN: 192408Hom.: 0 AF XY: 0.000364 AC XY: 37AN XY: 101632
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GnomAD4 exome AF: 0.000190 AC: 263AN: 1383088Hom.: 1 Cov.: 31 AF XY: 0.000165 AC XY: 112AN XY: 677884
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GnomAD4 genome ? AF: 0.00163 AC: 248AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112AN XY: 74458
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5Other:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 20, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2021 | This variant is associated with the following publications: (PMID: 22378279, 24055113, 25637381, 20129283, 26332594, 11997281, 24631775, 14760488, 28491593) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 04, 2021 | - - |
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:11997281;PMID:14760488;PMID:15840476;PMID:19841300;PMID:20129283;PMID:12673799;PMID:22378279). - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2015 | p.Leu618Phe in exon 12 of SCN5A: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (59/9220) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs45488304). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 29, 2018 | Variant summary: SCN5A c.1852C>T (p.Leu618Phe) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 216 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.1852C>T, has been reported in the literature in individuals affected with sudden unexplained death (SUD)( Wang_2014 ), Brugada syndrome (Amin_2009), atrial fibrillation (Darbar_2008), and long QT syndrome (Tester_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy, Brugada syndrome, atrial fibrillation, Long QT, or SCD. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Yang_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as Benign. - |
Brugada syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 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. - |
Long QT syndrome, drug-associated Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Cardiac arrhythmia Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
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
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
D;P;.;D;.;P;D;.;.
Vest4
MVP
MPC
0.90
ClinPred
T
GERP RS
Varity_R
gMVP
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