3-38604932-C-T

Variant names:

• chr3-38604932-C-T
• rs7428779
• NM_001099404.2:c.1339-24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099404.2(SCN5A):​c.1339-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,592,430 control chromosomes in the GnomAD database, including 29,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2697 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27185 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.846
• Publications: 10 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=-0.94).
• BP6: Variant 3-38604932-C-T is Benign according to our data. Variant chr3-38604932-C-T is described in ClinVar as Benign. ClinVar VariationId is 257437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.203 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.1339-24G>A		intron	N/A	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.1339-24G>A		intron	N/A	NP_000326.2
	SCN5A	NM_198056.3		c.1339-24G>A		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.1339-24G>A		intron	N/A	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1339-24G>A		intron	N/A	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.1339-24G>A		intron	N/A	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28410 AN: 152030 Hom.: 2689 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.0941

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.186 AC: 39952 AN: 214270 AF XY: 0.189

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0845

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.193 AC: 277865 AN: 1440282 Hom.: 27185 Cov.: 32 AF XY: 0.194 AC XY: 138586 AN XY: 714172

African (AFR) AF: 0.167 AC: 5509 AN: 33080

American (AMR) AF: 0.196 AC: 8096 AN: 41392

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3971 AN: 25608

East Asian (EAS) AF: 0.0891 AC: 3466 AN: 38914

South Asian (SAS) AF: 0.205 AC: 16993 AN: 82830

European-Finnish (FIN) AF: 0.176 AC: 9177 AN: 52162

Middle Eastern (MID) AF: 0.179 AC: 1024 AN: 5722

European-Non Finnish (NFE) AF: 0.198 AC: 218301 AN: 1100928

Other (OTH) AF: 0.190 AC: 11328 AN: 59646

GnomAD4 genome AF: 0.187 AC: 28452 AN: 152148 Hom.: 2697 Cov.: 32 AF XY: 0.189 AC XY: 14076 AN XY: 74382

African (AFR) AF: 0.169 AC: 7032 AN: 41498

American (AMR) AF: 0.194 AC: 2965 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 508 AN: 3468

East Asian (EAS) AF: 0.0943 AC: 488 AN: 5174

South Asian (SAS) AF: 0.214 AC: 1033 AN: 4832

European-Finnish (FIN) AF: 0.174 AC: 1848 AN: 10608

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13983 AN: 67990

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.196 Hom.: 1866

Bravo AF: 0.186

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.069
DANN	Benign	0.49
PhyloP100		-0.85
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: rs7428779; hg19: chr3-38646423; COSMIC: COSV61118038;