rs763891399

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000423572.7(SCN5A):ā€‹c.3080G>Cā€‹(p.Arg1027Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1027Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

1
6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.31542844).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.3080G>C p.Arg1027Pro missense_variant 17/28 ENST00000413689.6 NP_001092874.1
SCN5ANM_000335.5 linkuse as main transcriptc.3080G>C p.Arg1027Pro missense_variant 17/28 ENST00000423572.7 NP_000326.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.3080G>C p.Arg1027Pro missense_variant 17/285 NM_001099404.2 ENSP00000410257 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.3080G>C p.Arg1027Pro missense_variant 17/281 NM_000335.5 ENSP00000398266 A1Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248354
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134846
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461616
Hom.:
0
Cov.:
37
AF XY:
0.00000138
AC XY:
1
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
CardioboostCm
Benign
0.00058
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.53
.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.049
Eigen_PC
Benign
-0.093
FATHMM_MKL
Benign
0.56
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
0.93
.;L;.;.;.;L;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.6
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.25
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.34
T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;B;.;D;.;B;D;.;.
Vest4
0.23
MutPred
0.39
Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);Gain of loop (P = 0.0321);
MVP
0.91
MPC
0.26
ClinPred
0.73
D
GERP RS
5.1
Varity_R
0.42
gMVP
0.71

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: rs763891399; hg19: chr3-38622570; API