rs1805126

Variant names:

• chr3-38550915-A-G
• rs1805126
• NM_001099404.2:c.5457T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-38550915-A-G
• chr3-38550915-A-C
• chr3-38550915-A-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.5454T>C​(p.Asp1818Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,600 control chromosomes in the GnomAD database, including 110,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16131 hom., cov: 31)
  • Exomes 𝑓: 0.35 (94386 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -2.12
• Publications: 80 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=-0.83).
• BP6: Variant 3-38550915-A-G is Benign according to our data. Variant chr3-38550915-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 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.5457T>C	p.Asp1819Asp	synonymous	Exon 28 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.5454T>C	p.Asp1818Asp	synonymous	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.5457T>C	p.Asp1819Asp	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.5457T>C	p.Asp1819Asp	synonymous	Exon 28 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.5454T>C	p.Asp1818Asp	synonymous	Exon 28 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.5457T>C	p.Asp1819Asp	synonymous	Exon 28 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66453 AN: 151806 Hom.: 16085 Cov.: 31

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.387 AC: 96582 AN: 249672 AF XY: 0.379

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.353 AC: 515661 AN: 1461676 Hom.: 94386 Cov.: 65 AF XY: 0.351 AC XY: 255503 AN XY: 727116

African (AFR) AF: 0.663 AC: 22209 AN: 33480

American (AMR) AF: 0.377 AC: 16842 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9028 AN: 26136

East Asian (EAS) AF: 0.527 AC: 20906 AN: 39700

South Asian (SAS) AF: 0.335 AC: 28874 AN: 86258

European-Finnish (FIN) AF: 0.442 AC: 23580 AN: 53356

Middle Eastern (MID) AF: 0.433 AC: 2499 AN: 5768

European-Non Finnish (NFE) AF: 0.332 AC: 368838 AN: 1111880

Other (OTH) AF: 0.379 AC: 22885 AN: 60374

GnomAD4 genome AF: 0.438 AC: 66548 AN: 151924 Hom.: 16131 Cov.: 31 AF XY: 0.439 AC XY: 32609 AN XY: 74256

African (AFR) AF: 0.651 AC: 26957 AN: 41404

American (AMR) AF: 0.376 AC: 5739 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3472

East Asian (EAS) AF: 0.551 AC: 2827 AN: 5128

South Asian (SAS) AF: 0.327 AC: 1576 AN: 4814

European-Finnish (FIN) AF: 0.448 AC: 4728 AN: 10554

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22145 AN: 67966

Other (OTH) AF: 0.419 AC: 884 AN: 2112

Alfa AF: 0.368 Hom.: 47478

Bravo AF: 0.448

Asia WGS AF: 0.442 AC: 1539 AN: 3478

EpiCase AF: 0.342

EpiControl AF: 0.340

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.83
CADD	Benign	0.020
DANN	Benign	0.48
PhyloP100		-2.1
Mutation Taster		=99/1	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: rs1805126; hg19: chr3-38592406; COSMIC: COSV61133328; COSMIC: COSV61133328;