rs483353016

Variant names:

• chr3-38562414-C-A
• rs483353016
• NM_001099404.2:c.3963+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38562414-C-A
• chr3-38562414-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001099404.2(SCN5A):​c.3963+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.020327218 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 3-38562414-C-A is Pathogenic according to our data. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38562414-C-A is described in CliVar as Pathogenic. Clinvar id is 2026498.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3963+1G>T		splice_donor_variant, intron_variant	Intron 22 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3960+1G>T		splice_donor_variant, intron_variant	Intron 22 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3963+1G>T		splice_donor_variant, intron_variant	Intron 22 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3960+1G>T		splice_donor_variant, intron_variant	Intron 22 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 22 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Brugada syndrome (PMID: 20031634, 28341781). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
GERP RS		4.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs483353016; hg19: chr3-38603905;