NM_001099404.2:c.1141-3C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_001099404.2(SCN5A):c.1141-3C>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.18 in 1,612,096 control chromosomes in the GnomAD database, including 26,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2225 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24351 hom. )

Consequence

SCN5A
NM_001099404.2 splice_region, intron

Scores

Splicing: ADA: 0.9992

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 3.84

Publications

23 publications found

Variant links:

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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 3-38606151-G-T is Benign according to our data. Variant chr3-38606151-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCN5A	NM_001099404.2	MANE Plus Clinical	c.1141-3C>A	splice_region intron	N/A	NP_001092874.1	H9KVD2
SCN5A	NM_000335.5	MANE Select	c.1141-3C>A	splice_region intron	N/A	NP_000326.2
SCN5A	NM_198056.3		c.1141-3C>A	splice_region intron	N/A	NP_932173.1	Q14524-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.1141-3C>A	splice_region intron	N/A	ENSP00000410257.1	H9KVD2
SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1141-3C>A	splice_region intron	N/A	ENSP00000398266.2	Q14524-2
SCN5A	ENST00000333535.9	TSL:1	c.1141-3C>A	splice_region intron	N/A	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25593

AN:

151920

Hom.:

2225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.0968

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.173

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.168

GnomAD2 exomes

AF:

0.172

AC:

42640

AN:

248386

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.183

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.0894

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.187

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.181

AC:

264271

AN:

1460058

Hom.:

24351

Cov.:

AF XY:

0.182

AC XY:

131857

AN XY:

726366

show subpopulations

African (AFR)

AF:

0.122

AC:

4091

AN:

33458

American (AMR)

AF:

0.184

AC:

8220

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3768

AN:

26122

East Asian (EAS)

AF:

0.0902

AC:

3581

AN:

39696

South Asian (SAS)

AF:

0.173

AC:

14926

AN:

86202

European-Finnish (FIN)

AF:

0.175

AC:

9286

AN:

53072

Middle Eastern (MID)

AF:

0.162

AC:

904

AN:

5564

European-Non Finnish (NFE)

AF:

0.188

AC:

208932

AN:

1110968

Other (OTH)

AF:

0.175

AC:

10563

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

10093

20186

30279

40372

50465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7228

14456

21684

28912

36140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.168

AC:

25601

AN:

152038

Hom.:

2225

Cov.:

AF XY:

0.170

AC XY:

12661

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.128

AC:

5299

AN:

41470

American (AMR)

AF:

0.179

AC:

2733

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

473

AN:

3468

East Asian (EAS)

AF:

0.0968

AC:

500

AN:

5164

South Asian (SAS)

AF:

0.177

AC:

853

AN:

4814

European-Finnish (FIN)

AF:

0.173

AC:

1837

AN:

10590

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13362

AN:

67950

Other (OTH)

AF:

0.169

AC:

356

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1100

2201

3301

4402

5502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.176

Hom.:

1466

Bravo

AF:

0.165

Asia WGS

AF:

0.156

AC:

542

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.188

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (5)

Brugada syndrome 1 (2)

Cardiac arrhythmia (2)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Dilated cardiomyopathy 1E (1)

Long QT syndrome 3 (1)

Primary dilated cardiomyopathy (1)

Progressive familial heart block, type 1A (1)

Sick sinus syndrome 1 (1)

Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.8

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over