rs397763929

Variant names:

• chr3-38548867-C-CT
• rs397763929
• NM_001099404.2:c.*1453dupA

Your query was ambiguous. Multiple possible variants found:

• chr3-38548867-C-CT
• chr3-38548867-C-CTTATG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000335.5(SCN5A):​c.*1453dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,570 control chromosomes in the GnomAD database, including 6,170 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6166 hom., cov: 29)
  • Exomes 𝑓: 0.15 (4 hom.)
• Consequence: SCN5A NM_000335.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0610
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-38548867-C-CT is Benign according to our data. Variant chr3-38548867-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 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.*1453dupA		3_prime_UTR	Exon 28 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.*1453dupA		3_prime_UTR	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.*1453dupA		3_prime_UTR	Exon 28 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.*1453dupA		3_prime_UTR	Exon 28 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.*1453dupA		3_prime_UTR	Exon 28 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.*1453dupA		3_prime_UTR	Exon 28 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34606 AN: 152018 Hom.: 6128 Cov.: 29

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0910

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.147 AC: 64 AN: 434 Hom.: 4 Cov.: 0 AF XY: 0.134 AC XY: 35 AN XY: 262

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.147 AC: 59 AN: 402

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.192 AC: 5 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.228 AC: 34692 AN: 152136 Hom.: 6166 Cov.: 29 AF XY: 0.229 AC XY: 17054 AN XY: 74364

African (AFR) AF: 0.478 AC: 19811 AN: 41464

American (AMR) AF: 0.189 AC: 2885 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 418 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2334 AN: 5154

South Asian (SAS) AF: 0.158 AC: 762 AN: 4824

European-Finnish (FIN) AF: 0.166 AC: 1760 AN: 10612

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0910 AC: 6186 AN: 67986

Other (OTH) AF: 0.215 AC: 455 AN: 2116

Alfa AF: 0.165 Hom.: 447

Bravo AF: 0.244

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)
-	-	1	Paroxysmal familial ventricular fibrillation (1)
-	-	1	Progressive familial heart block (1)
-	-	1	Sick sinus syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061
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: rs397763929; hg19: chr3-38590358;