NM_001099404.2:c.3511+10C>T

Variant names:

• chr3-38576651-G-A
• rs41258454
• NM_001099404.2:c.3511+10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099404.2(SCN5A):​c.3511+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,610,348 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (35 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -1.21
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-38576651-G-A is Benign according to our data. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38576651-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 36760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00499 (760/152352) while in subpopulation NFE AF = 0.00789 (537/68022). AF 95% confidence interval is 0.00734. There are 3 homozygotes in GnomAd4. There are 347 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3511+10C>T		intron_variant	Intron 19 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3508+10C>T		intron_variant	Intron 19 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3511+10C>T		intron_variant	Intron 19 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3508+10C>T		intron_variant	Intron 19 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00471 AC: 1136 AN: 241080 AF XY: 0.00466

Gnomad AFR exome AF: 0.00238

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00615 AC: 8972 AN: 1457996 Hom.: 35 Cov.: 31 AF XY: 0.00605 AC XY: 4383 AN XY: 724716

African (AFR) AF: 0.00233 AC: 78 AN: 33444

American (AMR) AF: 0.00268 AC: 119 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00254 AC: 216 AN: 85088

European-Finnish (FIN) AF: 0.00348 AC: 185 AN: 53106

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5730

European-Non Finnish (NFE) AF: 0.00725 AC: 8048 AN: 1110424

Other (OTH) AF: 0.00530 AC: 319 AN: 60212

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74508

African (AFR) AF: 0.00351 AC: 146 AN: 41582

American (AMR) AF: 0.00163 AC: 25 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00789 AC: 537 AN: 68022

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00615 Hom.: 6

Bravo AF: 0.00425

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Mar 04, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.3511+10C>T in Intron 19 of SCN5A: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 0.6% (43/6870) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS; dbSNP rs41258454). -

not provided Benign:6

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Nov 10, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Brugada syndrome 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dilated cardiomyopathy 1E Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Brugada syndrome Benign:1

Jan 25, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sick sinus syndrome 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital heart disease Benign:1

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Progressive familial heart block, type 1A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Long QT syndrome 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.012
DANN	Benign	0.31
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41258454; hg19: chr3-38618142;