rs41261344

Variant names:

• chr3-38575385-C-T
• rs41261344
• NM_001099404.2:c.3578G>A

Variant summary

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

The NM_000335.5(SCN5A):​c.3575G>A​(p.Arg1192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,609,400 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R1192W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (87 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:20 O:2
• Conservation: PhyloP100: -0.186
• Publications: 110 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046313703).
• BP6: Variant 3-38575385-C-T is Benign according to our data. Variant chr3-38575385-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.051 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.3578G>A	p.Arg1193Gln	missense	Exon 20 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.3575G>A	p.Arg1192Gln	missense	Exon 20 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3578G>A	p.Arg1193Gln	missense	Exon 20 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.3578G>A	p.Arg1193Gln	missense	Exon 20 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3575G>A	p.Arg1192Gln	missense	Exon 20 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.3578G>A	p.Arg1193Gln	missense	Exon 20 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152166 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0571

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00535 AC: 1292 AN: 241456 AF XY: 0.00548

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0619

Gnomad FIN exome AF: 0.000951

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00285 AC: 4151 AN: 1457116 Hom.: 87 Cov.: 31 AF XY: 0.00276 AC XY: 1998 AN XY: 724366

African (AFR) AF: 0.000239 AC: 8 AN: 33422

American (AMR) AF: 0.000408 AC: 18 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.0611 AC: 2417 AN: 39544

South Asian (SAS) AF: 0.000868 AC: 74 AN: 85256

European-Finnish (FIN) AF: 0.00129 AC: 68 AN: 52736

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00110 AC: 1226 AN: 1109974

Other (OTH) AF: 0.00561 AC: 338 AN: 60226

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152284 Hom.: 6 Cov.: 33 AF XY: 0.00310 AC XY: 231 AN XY: 74456

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0563 AC: 291 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00331 Hom.: 28

Bravo AF: 0.00303

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00467 AC: 567

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	3	not specified (3)
1	-	1	Brugada syndrome 1 (2)
-	-	2	Long QT syndrome 3 (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1E (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)
-	-	1	Progressive familial heart block, type 1A (1)
-	-	1	Sick sinus syndrome 1 (1)
-	-	1	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 (1)
-	-	1	Ventricular fibrillation, paroxysmal familial, type 1 (1)
-	-	-	Long QT syndrome 3, acquired, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.19
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.31
Sift	Benign	0.37	T
Sift4G	Benign	0.10	T
Polyphen		0.0030	B
Vest4		0.41
MVP		0.48
MPC		0.60
ClinPred		0.027	T
GERP RS		1.6
Varity_R		0.049
gMVP		0.77
Mutation Taster		=97/3	polymorphism

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: rs41261344; hg19: chr3-38616876; COSMIC: COSV61138280;