3-38599058-C-T

Position:

chr3-38599058-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000423572.7(SCN5A):c.1891-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,594,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.002486

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.768

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 3-38599058-C-T is Benign according to our data. Variant chr3-38599058-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165153.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5 linkuse as main transcript	c.1891-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2 linkuse as main transcript	c.1891-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_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.1891-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1891-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000289

AC:

AN:

242618

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

131926

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.0000293

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:

0.0000173

AC:

AN:

1442104

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

712894

show subpopulations

Gnomad4 AFR exome

AF:

0.000664

Gnomad4 AMR exome

AF:

0.0000226

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:

0.0000337

GnomAD4 genome

AF:

0.000118

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0000654

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:

0.000102

Hom.:

Bravo

AF:

0.000125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2017	The c.1891-8G>A variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 10/23702 of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs12720064). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1891-8G>A variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richar ds 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2017	Variant summary: The SCN5A c.1891-8G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/270732 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000422 (10/23702). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, two clinical diagnostic laboratories classified this variant as likely benign and one other lab classified it as uncertain significance, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiac arrhythmia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 03, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2018	- -

Brugada syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

in vitro;research

Roden Lab, Vanderbilt University Medical Center

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868). The SCN5A variant, 3-38599058-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome. This Variant had an AF of 0.000118295 in gnomAD v3. The in silico predictor SpliceAI scored the variant as 0.01; normal <0.2, likely damaging >0.5. Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as LB using these collective data. -

SCN5A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.9

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.086

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.

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