rs191009474

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate

The ENST00000423572.7(SCN5A):​c.1019G>T​(p.Arg340Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SCN5A
ENST00000423572.7 missense

Scores

1
4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.351
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 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000423572.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38606790-C-T is described in Lovd as [Likely_pathogenic].
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=0.21286625).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.1019G>T p.Arg340Leu missense_variant 9/28 ENST00000413689.6 NP_001092874.1
SCN5ANM_000335.5 linkuse as main transcriptc.1019G>T p.Arg340Leu missense_variant 9/28 ENST00000423572.7 NP_000326.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.1019G>T p.Arg340Leu missense_variant 9/285 NM_001099404.2 ENSP00000410257 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.1019G>T p.Arg340Leu missense_variant 9/281 NM_000335.5 ENSP00000398266 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152234
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152352
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
CardioboostCm
Benign
0.0040
BayesDel_addAF
Uncertain
0.081
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.58
.;T;T;T;T;T;T;.;T
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
-0.14
.;N;.;.;.;N;.;.;.
MutationTaster
Benign
0.85
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.73
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.30
Sift
Benign
0.46
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.76
T;T;T;T;T;T;T;T;T
Polyphen
0.0010
B;B;.;B;.;B;B;.;.
Vest4
0.46
MVP
0.35
MPC
0.44
ClinPred
0.16
T
GERP RS
2.8
Varity_R
0.099
gMVP
0.93

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: rs191009474; hg19: chr3-38648281; API