rs41260344

chr3-38581377-G-Achr3-38581377-G-Cchr3-38581377-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099404.2(SCN5A):c.2788-6C>T 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 0.0377 in 1,578,788 control chromosomes in the GnomAD database, including 1,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (182 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1169 hom.)
• Consequence: SCN5A NM_001099404.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009660
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.276

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 3-38581377-G-A is Benign according to our data. Variant chr3-38581377-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38581377-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.2788-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.2788-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2788-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2788-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6290 AN: 152032 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0326 AC: 7369 AN: 226216 Hom.: 157 AF XY: 0.0334 AC XY: 4071 AN XY: 121790

Gnomad AFR exome AF: 0.0532

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0384

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.0363

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0386

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0373 AC: 53256 AN: 1426638 Hom.: 1169 Cov.: 36 AF XY: 0.0376 AC XY: 26476 AN XY: 703888

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.0187

Gnomad4 ASJ exome AF: 0.0386

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0352

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0398

GnomAD4 genome AF: 0.0414 AC: 6304 AN: 152150 Hom.: 182 Cov.: 32 AF XY: 0.0394 AC XY: 2932 AN XY: 74400

Gnomad4 AFR AF: 0.0554

Gnomad4 AMR AF: 0.0313

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0404 Hom.: 48

Bravo AF: 0.0418

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.2788-6C>T in Intron 16 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 5.1% (185/3632) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs41260344). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiac arrhythmia Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -

Brugada syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Dilated cardiomyopathy 1E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Sick sinus syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Progressive familial heart block, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary dilated cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 27, 2022

- -

Long QT syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.6
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs41260344; hg19: chr3-38622868; COSMIC: COSV104658849;