rs758282196

Variant names:

• chr3-38580942-ACTC-A
• rs758282196
• NM_001099404.2:c.3214_3216delGAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000335.5(SCN5A):​c.3214_3216delGAG​(p.Glu1072del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000483 in 1,448,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_000335.5 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.01
• 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: Orphanet, ClinGen
• Brugada syndrome 1

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

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

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• progressive familial heart block, type 1A

  Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• sick sinus syndrome 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• 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
• congenital heart disease

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000335.5. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000335.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	NP_932173.1	Q14524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.3214_3216delGAG	p.Glu1072del	conservative_inframe_deletion	Exon 17 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244388 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1448272 Hom.: 0 AF XY: 0.00000557 AC XY: 4 AN XY: 717690

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1101952

Other (OTH) AF: 0.00 AC: 0 AN: 59704

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiac arrhythmia (2)
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

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: rs758282196; hg19: chr3-38622433;