rs13084981

Variant names:

• chr3-38604508-C-T
• rs13084981
• NM_001099404.2:c.1518+221G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-38604508-C-T
• chr3-38604508-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000335.5(SCN5A):​c.1518+221G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,146 control chromosomes in the GnomAD database, including 1,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1548 hom., cov: 32)
• Consequence: SCN5A NM_000335.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0870
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-38604508-C-T is Benign according to our data. Variant chr3-38604508-C-T is described in ClinVar as Benign. ClinVar VariationId is 678651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 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.1518+221G>A		intron	N/A	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.1518+221G>A		intron	N/A	NP_000326.2
	SCN5A	NM_198056.3		c.1518+221G>A		intron	N/A	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.1518+221G>A		intron	N/A	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1518+221G>A		intron	N/A	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.1518+221G>A		intron	N/A	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19058 AN: 152028 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0877

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.132

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

GnomAD4 genome AF: 0.125 AC: 19066 AN: 152146 Hom.: 1548 Cov.: 32 AF XY: 0.131 AC XY: 9719 AN XY: 74356

African (AFR) AF: 0.0943 AC: 3916 AN: 41546

American (AMR) AF: 0.124 AC: 1888 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 304 AN: 3468

East Asian (EAS) AF: 0.478 AC: 2446 AN: 5116

South Asian (SAS) AF: 0.173 AC: 835 AN: 4822

European-Finnish (FIN) AF: 0.183 AC: 1934 AN: 10596

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7344 AN: 67994

Other (OTH) AF: 0.132 AC: 279 AN: 2116

Alfa AF: 0.112 Hom.: 1190

Bravo AF: 0.122

Asia WGS AF: 0.290 AC: 1005 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.63
PhyloP100		0.087
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: rs13084981; hg19: chr3-38645999;