rs41315495

Variant names:

• chr3-38551524-G-A
• rs41315495
• NM_001099404.2:c.4848C>T

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.4845C>T​(p.Phe1615Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00921 in 1,604,960 control chromosomes in the GnomAD database, including 1,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (606 hom., cov: 30)
  • Exomes 𝑓: 0.0051 (510 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 2.78
• Publications: 6 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=-0.47).
• BP6: Variant 3-38551524-G-A is Benign according to our data. Variant chr3-38551524-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 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.4848C>T	p.Phe1616Phe	synonymous	Exon 28 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.4845C>T	p.Phe1615Phe	synonymous	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.4848C>T	p.Phe1616Phe	synonymous	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.4848C>T	p.Phe1616Phe	synonymous	Exon 28 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4845C>T	p.Phe1615Phe	synonymous	Exon 28 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.4848C>T	p.Phe1616Phe	synonymous	Exon 28 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7296 AN: 143534 Hom.: 605 Cov.: 30

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.000303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.000803

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0129 AC: 3241 AN: 250856 AF XY: 0.00957

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000538

Gnomad OTH exome AF: 0.00801

GnomAD4 exome AF: 0.00512 AC: 7479 AN: 1461300 Hom.: 510 Cov.: 34 AF XY: 0.00444 AC XY: 3228 AN XY: 726930

African (AFR) AF: 0.170 AC: 5687 AN: 33424

American (AMR) AF: 0.0110 AC: 491 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5766

European-Non Finnish (NFE) AF: 0.000472 AC: 525 AN: 1111700

Other (OTH) AF: 0.0110 AC: 665 AN: 60328

GnomAD4 genome AF: 0.0508 AC: 7303 AN: 143660 Hom.: 606 Cov.: 30 AF XY: 0.0488 AC XY: 3429 AN XY: 70338

African (AFR) AF: 0.177 AC: 6851 AN: 38722

American (AMR) AF: 0.0217 AC: 315 AN: 14542

Ashkenazi Jewish (ASJ) AF: 0.000303 AC: 1 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 4768

South Asian (SAS) AF: 0.000898 AC: 4 AN: 4456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10010

Middle Eastern (MID) AF: 0.0128 AC: 3 AN: 234

European-Non Finnish (NFE) AF: 0.000803 AC: 52 AN: 64772

Other (OTH) AF: 0.0388 AC: 77 AN: 1984

Alfa AF: 0.0420 Hom.: 366

Bravo AF: 0.0552

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Brugada syndrome (1)
-	-	1	Brugada syndrome 1 (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	-0.47
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41315495; hg19: chr3-38593015;