3-38606571-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001099404.2(SCN5A):c.1140+98G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,409,404 control chromosomes in the GnomAD database, including 455,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49377 hom., cov: 34)

Exomes 𝑓: 0.80 ( 406052 hom. )

Consequence

SCN5A
NM_001099404.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.102

Publications

16 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: 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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 3-38606571-C-T is Benign according to our data. Variant chr3-38606571-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1140+98G>A		intron_variant	Intron 9 of 27	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1140+98G>A		intron_variant	Intron 9 of 27	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.1140+98G>A		intron_variant	Intron 9 of 27	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1140+98G>A		intron_variant	Intron 9 of 27	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122321

AN:

152094

Hom.:

49327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.766

Gnomad AMR

AF:

0.813

Gnomad ASJ

AF:

0.800

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.868

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.794

Gnomad OTH

AF:

0.811

GnomAD4 exome

AF:

0.803

AC:

1008948

AN:

1257192

Hom.:

406052

AF XY:

0.804

AC XY:

498733

AN XY:

620146

show subpopulations

African (AFR)

AF:

0.779

AC:

22361

AN:

28706

American (AMR)

AF:

0.839

AC:

27574

AN:

32846

Ashkenazi Jewish (ASJ)

AF:

0.798

AC:

18127

AN:

22714

East Asian (EAS)

AF:

0.972

AC:

33836

AN:

34806

South Asian (SAS)

AF:

0.865

AC:

62616

AN:

72394

European-Finnish (FIN)

AF:

0.808

AC:

32160

AN:

39796

Middle Eastern (MID)

AF:

0.816

AC:

3674

AN:

4504

European-Non Finnish (NFE)

AF:

0.791

AC:

765744

AN:

968376

Other (OTH)

AF:

0.808

AC:

42856

AN:

53050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

9403

18805

28208

37610

47013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18016

36032

54048

72064

90080

<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:

0.804

AC:

122429

AN:

152212

Hom.:

49377

Cov.:

AF XY:

0.809

AC XY:

60215

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.786

AC:

32639

AN:

41520

American (AMR)

AF:

0.813

AC:

12441

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.800

AC:

2777

AN:

3470

East Asian (EAS)

AF:

0.984

AC:

5095

AN:

5178

South Asian (SAS)

AF:

0.868

AC:

4186

AN:

4822

European-Finnish (FIN)

AF:

0.812

AC:

8610

AN:

10600

Middle Eastern (MID)

AF:

0.827

AC:

243

AN:

294

European-Non Finnish (NFE)

AF:

0.794

AC:

54018

AN:

68002

Other (OTH)

AF:

0.814

AC:

1721

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1259

2519

3778

5038

6297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.794

Hom.:

150671

Bravo

AF:

0.800

Asia WGS

AF:

0.909

AC:

3159

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.1

(source)

DANN

Benign

0.69

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over