3-38565865-A-G

Variant names:

• chr3-38565865-A-G
• rs7372251
• NM_001099404.2:c.3840+544T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001099404.2(SCN5A):​c.3840+544T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 151,916 control chromosomes in the GnomAD database, including 17,946 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (17946 hom., cov: 32)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.833
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.3840+544T>C		intron	N/A	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.3837+544T>C		intron	N/A	NP_000326.2
	SCN5A	NM_198056.3		c.3840+544T>C		intron	N/A	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.3840+544T>C		intron	N/A	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3837+544T>C		intron	N/A	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.3840+544T>C		intron	N/A	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70029 AN: 151798 Hom.: 17946 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.497

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.461 AC: 70069 AN: 151916 Hom.: 17946 Cov.: 32 AF XY: 0.466 AC XY: 34607 AN XY: 74232

African (AFR) AF: 0.229 AC: 9487 AN: 41426

American (AMR) AF: 0.500 AC: 7639 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1966 AN: 3470

East Asian (EAS) AF: 0.854 AC: 4363 AN: 5110

South Asian (SAS) AF: 0.608 AC: 2928 AN: 4818

European-Finnish (FIN) AF: 0.523 AC: 5522 AN: 10568

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36611 AN: 67934

Other (OTH) AF: 0.498 AC: 1047 AN: 2104

Alfa AF: 0.475 Hom.: 2226

Bravo AF: 0.447

Asia WGS AF: 0.655 AC: 2276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.3
DANN	Benign	0.73
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs7372251; hg19: chr3-38607356;