rs1438675647

Variant summary

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

The ENST00000423572.7(SCN5A):โ€‹c.2081A>Gโ€‹(p.Tyr694Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (โ˜…โ˜…). Synonymous variant affecting the same amino acid position (i.e. Y694Y) has been classified as Likely benign.

Frequency

Genomes: ๐‘“ 0.000013 ( 0 hom., cov: 32)
Exomes ๐‘“: 6.8e-7 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

2
10
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.878
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.

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=0.42273694).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.2081A>G p.Tyr694Cys missense_variant 14/28 ENST00000413689.6 NP_001092874.1
SCN5ANM_000335.5 linkuse as main transcriptc.2081A>G p.Tyr694Cys missense_variant 14/28 ENST00000423572.7 NP_000326.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.2081A>G p.Tyr694Cys missense_variant 14/285 NM_001099404.2 ENSP00000410257 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.2081A>G p.Tyr694Cys missense_variant 14/281 NM_000335.5 ENSP00000398266 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249120
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135140
show subpopulations
Gnomad AFR exome
AF:
0.0000646
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461680
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 19, 2022Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 21, 2023An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variantยฌโ€  is likely to be tolerated. 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. This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 532115). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 694 of the SCN5A protein (p.Tyr694Cys). -
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 18, 2023This missense variant replaces tyrosine with cysteine at codon 694 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with postpartum cardiomyopathy (PMID: 33874732). This variant has been identified in 2/280524 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. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 01, 2023This missense variant replaces tyrosine with cysteine at codon 694 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with postpartum cardiomyopathy (PMID: 33874732). This variant has been identified in 2/280524 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 31, 2020Variant summary: SCN5A c.2081A>G (p.Tyr694Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249120 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2081A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 13, 2024The p.Y694C variant (also known as c.2081A>G), located in coding exon 13 of the SCN5A gene, results from an A to G substitution at nucleotide position 2081. The tyrosine at codon 694 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a peripartum cardiomyopathy cohort; however, details were limited (Goli R et al. Circulation, 2021 May;143:1852-1862). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
CardioboostCm
Benign
0.0010
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.43
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.88
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.1
.;M;.;.;.;M;.;.;.
MutationTaster
Benign
0.93
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-4.4
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.57
Sift
Benign
0.26
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.11
T;T;T;T;T;T;T;T;T
Polyphen
0.0070
B;B;.;B;.;B;B;.;.
Vest4
0.49
MVP
0.90
MPC
0.45
ClinPred
0.15
T
GERP RS
2.4
Varity_R
0.17
gMVP
0.95

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: rs1438675647; hg19: chr3-38639401; API