3-38580976-T-C

Variant names:

• chr3-38580976-T-C
• rs7430407
• NM_001099404.2:c.3183A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000335.5(SCN5A):​c.3183A>G​(p.Glu1061Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 1,611,390 control chromosomes in the GnomAD database, including 650,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61609 hom., cov: 34)
  • Exomes 𝑓: 0.90 (588804 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -1.09
• Publications: 49 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-38580976-T-C is Benign according to our data. Variant chr3-38580976-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.3183A>G	p.Glu1061Glu	synonymous	Exon 17 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.3183A>G	p.Glu1061Glu	synonymous	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3183A>G	p.Glu1061Glu	synonymous	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.3183A>G	p.Glu1061Glu	synonymous	Exon 17 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3183A>G	p.Glu1061Glu	synonymous	Exon 17 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.3183A>G	p.Glu1061Glu	synonymous	Exon 17 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136848 AN: 152204 Hom.: 61576 Cov.: 34

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.787

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.891

Gnomad OTH AF: 0.897

GnomAD2 exomes AF: 0.914 AC: 227155 AN: 248548 AF XY: 0.914

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.889

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.898 AC: 1310144 AN: 1459068 Hom.: 588804 Cov.: 65 AF XY: 0.899 AC XY: 652154 AN XY: 725204

African (AFR) AF: 0.883 AC: 29509 AN: 33434

American (AMR) AF: 0.942 AC: 42061 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 22474 AN: 26094

East Asian (EAS) AF: 0.999 AC: 39612 AN: 39634

South Asian (SAS) AF: 0.941 AC: 81112 AN: 86184

European-Finnish (FIN) AF: 0.923 AC: 49262 AN: 53370

Middle Eastern (MID) AF: 0.893 AC: 5145 AN: 5760

European-Non Finnish (NFE) AF: 0.889 AC: 987059 AN: 1109710

Other (OTH) AF: 0.895 AC: 53910 AN: 60228

GnomAD4 genome AF: 0.899 AC: 136934 AN: 152322 Hom.: 61609 Cov.: 34 AF XY: 0.904 AC XY: 67354 AN XY: 74484

African (AFR) AF: 0.887 AC: 36865 AN: 41570

American (AMR) AF: 0.912 AC: 13965 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2995 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5177 AN: 5184

South Asian (SAS) AF: 0.951 AC: 4592 AN: 4830

European-Finnish (FIN) AF: 0.929 AC: 9872 AN: 10624

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.891 AC: 60588 AN: 68016

Other (OTH) AF: 0.897 AC: 1897 AN: 2114

Alfa AF: 0.892 Hom.: 163110

Bravo AF: 0.898

Asia WGS AF: 0.958 AC: 3332 AN: 3478

EpiCase AF: 0.887

EpiControl AF: 0.891

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Dilated cardiomyopathy 1E (1)
-	-	1	Long QT syndrome 3 (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Progressive familial heart block, type 1A (1)
-	-	1	Sick sinus syndrome 1 (1)
-	-	1	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.7
DANN	Benign	0.39
PhyloP100		-1.1
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: rs7430407; hg19: chr3-38622467; COSMIC: COSV61125864;