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rs36210423

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM2PM5PP2BP4_StrongBP6

The NM_001099404.2(SCN5A):c.1715C>T(p.Ala572Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A572F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

4
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2O:1

Conservation

PhyloP100: 0.497
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38603887-G-T is described in Lovd as [Pathogenic].
PP2
Missense variant where missense usually causes diseases, SCN5A
BP4
Computational evidence support a benign effect (MetaRNN=0.00875482).
BP6
Variant 3-38603887-G-A is Benign according to our data. Variant chr3-38603887-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67684.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.1715C>T p.Ala572Val missense_variant 12/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.1715C>T p.Ala572Val missense_variant 12/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.1715C>T p.Ala572Val missense_variant 12/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.1715C>T p.Ala572Val missense_variant 12/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.000742
AC:
113
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00224
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000209
AC:
52
AN:
248994
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135080
show subpopulations
Gnomad AFR exome
AF:
0.00200
Gnomad AMR exome
AF:
0.000463
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:
0.0000266
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.0000842
AC:
123
AN:
1461636
Hom.:
0
Cov.:
31
AF XY:
0.0000770
AC XY:
56
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.00236
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000742
AC:
113
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.000779
AC XY:
58
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00224
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000778
ExAC
AF:
0.000190
AC:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 31, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported by 1 paper; ExAC: 0.2% (19/9772) African -
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 25, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeFeb 21, 2023- -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
CardioboostArm
Benign
0.000066
CardioboostCm
Benign
0.00055
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.020
Cadd
Benign
14
Dann
Uncertain
0.99
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.36
N
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.0088
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.50
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.37
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.29
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.53
T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;.;B;B;.;.
Vest4
0.67
MVP
0.97
MPC
0.35
ClinPred
0.010
T
GERP RS
3.2
Varity_R
0.033
gMVP
0.66

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: rs36210423; hg19: chr3-38645378; API