rs6599230

Variant names:

• chr3-38633221-T-C
• rs6599230
• NM_001099404.2:c.87A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-38633221-T-C
• chr3-38633221-T-A

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.87A>G​(p.Ala29Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,612,834 control chromosomes in the GnomAD database, including 502,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49149 hom., cov: 29)
  • Exomes 𝑓: 0.79 (453751 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -4.87
• Publications: 47 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=-0.93).
• BP6: Variant 3-38633221-T-C is Benign according to our data. Variant chr3-38633221-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 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.87A>G	p.Ala29Ala	synonymous	Exon 2 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.87A>G	p.Ala29Ala	synonymous	Exon 2 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.87A>G	p.Ala29Ala	synonymous	Exon 2 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.87A>G	p.Ala29Ala	synonymous	Exon 2 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.87A>G	p.Ala29Ala	synonymous	Exon 2 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.87A>G	p.Ala29Ala	synonymous	Exon 2 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121667 AN: 151850 Hom.: 49086 Cov.: 29

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.766 AC: 190293 AN: 248520 AF XY: 0.766

Gnomad AFR exome AF: 0.897

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.749

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.759

GnomAD4 exome AF: 0.787 AC: 1149738 AN: 1460866 Hom.: 453751 Cov.: 60 AF XY: 0.786 AC XY: 571164 AN XY: 726748

African (AFR) AF: 0.900 AC: 30119 AN: 33476

American (AMR) AF: 0.715 AC: 31961 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 19607 AN: 26130

East Asian (EAS) AF: 0.670 AC: 26589 AN: 39692

South Asian (SAS) AF: 0.746 AC: 64330 AN: 86238

European-Finnish (FIN) AF: 0.705 AC: 37243 AN: 52846

Middle Eastern (MID) AF: 0.703 AC: 3997 AN: 5682

European-Non Finnish (NFE) AF: 0.799 AC: 888764 AN: 1111744

Other (OTH) AF: 0.781 AC: 47128 AN: 60360

GnomAD4 genome AF: 0.801 AC: 121794 AN: 151968 Hom.: 49149 Cov.: 29 AF XY: 0.792 AC XY: 58820 AN XY: 74248

African (AFR) AF: 0.897 AC: 37191 AN: 41484

American (AMR) AF: 0.724 AC: 11060 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2616 AN: 3468

East Asian (EAS) AF: 0.684 AC: 3507 AN: 5124

South Asian (SAS) AF: 0.743 AC: 3548 AN: 4778

European-Finnish (FIN) AF: 0.688 AC: 7272 AN: 10564

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53939 AN: 67950

Other (OTH) AF: 0.808 AC: 1707 AN: 2112

Alfa AF: 0.800 Hom.: 99519

Bravo AF: 0.813

Asia WGS AF: 0.717 AC: 2494 AN: 3478

EpiCase AF: 0.799

EpiControl AF: 0.798

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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 (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	-0.93
CADD	Benign	0.19
DANN	Benign	0.24
PhyloP100		-4.9
PromoterAI		0.047	Neutral
Mutation Taster		=98/2	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: rs6599230; hg19: chr3-38674712; COSMIC: COSV60067473; COSMIC: COSV60067473;