3-38622490-G-A

Position:

chr3-38622490-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_001099404.2(SCN5A):c.393-1C>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000623 in 1,605,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 splice_acceptor

Scores

Splicing: ADA: 0.07055

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 4.12

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]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014708312 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38622490-G-A is Pathogenic according to our data. Variant chr3-38622490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517200.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5 linkuse as main transcript	c.393-1C>T		splice_acceptor_variant		ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2 linkuse as main transcript	c.393-1C>T		splice_acceptor_variant		ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.393-1C>T		splice_acceptor_variant		5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.393-1C>T		splice_acceptor_variant		1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

235338

Hom.:

AF XY:

0.0000157

AC XY:

AN XY:

127420

show subpopulations

Gnomad AFR exome

AF:

0.000140

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:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453110

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

722030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change affects an acceptor splice site in intron 3 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Brugada syndrome (PMID: 21321465). ClinVar contains an entry for this variant (Variation ID: 517200). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2024	Reported in an individual with Brugada syndrome, but it is unknown whether this individual was screened for variants in other genes associated with Brugada syndrome (PMID: 21321465); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 32573973, 33087929, 30662450, 31447099, 21321465, 34671977) -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This variant alters the intron 3 splice acceptor site of the SCN5A gene. This splice acceptor site uses AC, instead of the canonical AG, and is not recognized by computational algorithms that predict potential impact on splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 21321465) and in seven individuals participated in population-based studies whose clinical information was not available (PMID: 30420678, 3142281, 31447099, 32355288). This variant has also been identified in 5/266690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may disrupt normal splicing and adversely affect protein function, 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 submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2023	This variant alters the intron 3 splice acceptor site of the SCN5A gene. This splice acceptor site uses AC, instead of the canonical AG, and is not recognized by computational algorithms that predict potential impact on splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 21321465) and in seven individuals participated in population-based studies whose clinical information was not available (PMID: 30420678, 3142281, 31447099, 32355288). This variant has also been identified in 5/266690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may disrupt normal splicing and adversely affect protein function, 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. -

SCN5A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jun 04, 2024

PVS1, PM2 -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

The c.393-1C>T intronic variant results from a C to T substitution one nucleotide upstream from coding exon 3 of the SCN5A gene. This alteration impacts a splice site processed by the U12-spliceosome. Splice sites of U12-introns are not predicted well by in silico tools, but this alteration changes a key nucleotide in the U12 acceptor splice site consensus sequence. As such, this alteration is expected to cause aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown, but the impacted region is critical for protein function (Ambry internal data). This variant has been detected in an individual presenting with syncope who had Brugada pattern on ECG with sodium channel blocker challenge, and inducible ventricular fibrillation (Nakajima T et al. Int Heart J, 2011;52:27-31). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 17, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The c.393-1C>T variant in SCN5A has been reported in1 individual with suspected Brugada syndrome (Nakajima 2011). It has also been identified in 0.009% (2/23002) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) which typically cause altered splicing leading to an abnormal or absent protein. However, computational tools do not predict a splicing impact and exon 4 is in-frame, though this information is not predictive enough to rule out pathogenicity. Splice and other loss of function variants in SCN5A are most commonly associated with Brugada syndrome although overlap presentations including other SCN5A-related phenotypes (Long QT syndrome) have been described (Remme 2013). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

GERP RS

3.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.071

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over