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rs7626962

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM5PP2BP4

The NM_001099404.2(SCN5A):c.3308C>T(p.Ser1103Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1103Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.35
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38579416-G-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant where missense usually causes diseases, SCN5A
BP4
Computational evidence support a benign effect (MetaRNN=0.3208897).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.3308C>T p.Ser1103Phe missense_variant 18/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.3305C>T p.Ser1102Phe missense_variant 18/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.3308C>T p.Ser1103Phe missense_variant 18/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.3305C>T p.Ser1102Phe missense_variant 18/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000163
AC:
4
AN:
246002
Hom.:
0
AF XY:
0.00000746
AC XY:
1
AN XY:
134128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000360
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1460126
Hom.:
0
Cov.:
31
AF XY:
0.0000275
AC XY:
20
AN XY:
726272
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 27, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 23, 2019- -
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 20, 2022This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1103 of the SCN5A protein (p.Ser1103Phe). This variant is present in population databases (rs7626962, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 926646). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 09, 2023This missense variant replaces serine with phenylalanine at codon 1103 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/246002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
CardioboostArm
Benign
0.00010
CardioboostCm
Benign
0.0012
BayesDel_addAF
Benign
0.00014
T
BayesDel_noAF
Benign
-0.11
Cadd
Benign
22
Dann
Uncertain
0.98
Eigen
Benign
0.14
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.82
D
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.32
T;T;T;T;T;T
MetaSVM
Uncertain
0.090
D
MutationTaster
Benign
0.93
D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
-1.9
N;N;N;N;N;N
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Benign
0.070
T;T;T;T;T;T
Polyphen
0.27
B;B;.;B;B;B
Vest4
0.22
MutPred
0.22
Loss of phosphorylation at S1103 (P = 0.0098);.;Loss of phosphorylation at S1103 (P = 0.0098);Loss of phosphorylation at S1103 (P = 0.0098);Loss of phosphorylation at S1103 (P = 0.0098);.;
MVP
0.56
MPC
0.066
ClinPred
0.36
T
GERP RS
4.3
Varity_R
0.20
gMVP
0.62

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: rs7626962; hg19: chr3-38620907; API