rs1805124

Variant names:

• chr3-38603929-T-C
• rs1805124
• NM_001099404.2:c.1673A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198056.3(SCN5A):​c.1673A>G​(p.His558Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,720 control chromosomes in the GnomAD database, including 43,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H558Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4753 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39221 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:29 O:1
• Conservation: PhyloP100: 1.28
• Publications: 294 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: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• 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
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002580464).
• BP6: Variant 3-38603929-T-C is Benign according to our data. Variant chr3-38603929-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198056.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.1673A>G	p.His558Arg	missense	Exon 12 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.1673A>G	p.His558Arg	missense	Exon 12 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.1673A>G	p.His558Arg	missense	Exon 12 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.1673A>G	p.His558Arg	missense	Exon 12 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1673A>G	p.His558Arg	missense	Exon 12 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.1673A>G	p.His558Arg	missense	Exon 12 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37263 AN: 151978 Hom.: 4732 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.220 AC: 54882 AN: 249044 AF XY: 0.223

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.0933

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.230 AC: 335541 AN: 1461624 Hom.: 39221 Cov.: 35 AF XY: 0.231 AC XY: 167767 AN XY: 727106

African (AFR) AF: 0.294 AC: 9858 AN: 33480

American (AMR) AF: 0.219 AC: 9807 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5142 AN: 26124

East Asian (EAS) AF: 0.0938 AC: 3724 AN: 39700

South Asian (SAS) AF: 0.240 AC: 20744 AN: 86258

European-Finnish (FIN) AF: 0.199 AC: 10636 AN: 53366

Middle Eastern (MID) AF: 0.236 AC: 1362 AN: 5768

European-Non Finnish (NFE) AF: 0.234 AC: 260227 AN: 1111852

Other (OTH) AF: 0.233 AC: 14041 AN: 60370

GnomAD4 genome AF: 0.246 AC: 37344 AN: 152096 Hom.: 4753 Cov.: 32 AF XY: 0.245 AC XY: 18242 AN XY: 74342

African (AFR) AF: 0.294 AC: 12214 AN: 41528

American (AMR) AF: 0.230 AC: 3519 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3470

East Asian (EAS) AF: 0.101 AC: 522 AN: 5152

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4810

European-Finnish (FIN) AF: 0.197 AC: 2084 AN: 10578

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16303 AN: 67950

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.236 Hom.: 19484

Bravo AF: 0.249

TwinsUK AF: 0.234 AC: 869

ALSPAC AF: 0.230 AC: 885

ESP6500AA AF: 0.275 AC: 1151

ESP6500EA AF: 0.232 AC: 1957

ExAC AF: 0.221 AC: 26760

Asia WGS AF: 0.202 AC: 702 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.234

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
1	-	6	not provided (8)
-	-	3	Brugada syndrome 1 (3)
-	-	2	SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 (2)
-	-	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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	1.1
DANN	Benign	0.29
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.6	N
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.9	N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.42
ClinPred		0.0038	T
GERP RS		2.4
Varity_R		0.032
gMVP		0.70
Mutation Taster		=81/19	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: rs1805124; hg19: chr3-38645420; COSMIC: COSV61125544;