ENST00000491944.1:n.868T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000491944.1(SCN5A):n.868T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 155,130 control chromosomes in the GnomAD database, including 29,370 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 28779 hom., cov: 33)

Exomes 𝑓: 0.61 ( 591 hom. )

Consequence

SCN5A
ENST00000491944.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.160

Publications

14 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.612-476T>C		intron_variant	Intron 5 of 27	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.612-708T>C		intron_variant	Intron 5 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.612-476T>C		intron_variant	Intron 5 of 27	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.612-708T>C		intron_variant	Intron 5 of 27	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92832

AN:

151942

Hom.:

28739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.529

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.585

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.538

Gnomad FIN

AF:

0.561

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.600

Gnomad OTH

AF:

0.585

GnomAD4 exome

AF:

0.609

AC:

1870

AN:

3070

Hom.:

591

Cov.:

AF XY:

0.596

AC XY:

1002

AN XY:

1680

show subpopulations

African (AFR)

AF:

0.800

AC:

AN:

American (AMR)

AF:

0.633

AC:

272

AN:

430

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

AN:

East Asian (EAS)

AF:

0.300

AC:

AN:

South Asian (SAS)

AF:

0.600

AC:

AN:

120

European-Finnish (FIN)

AF:

0.565

AC:

252

AN:

446

Middle Eastern (MID)

AF:

0.833

AC:

AN:

European-Non Finnish (NFE)

AF:

0.625

AC:

1097

AN:

1756

Other (OTH)

AF:

0.576

AC:

AN:

132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.611

AC:

92922

AN:

152060

Hom.:

28779

Cov.:

AF XY:

0.606

AC XY:

44998

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.684

AC:

28399

AN:

41490

American (AMR)

AF:

0.619

AC:

9460

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

2028

AN:

3468

East Asian (EAS)

AF:

0.357

AC:

1846

AN:

5164

South Asian (SAS)

AF:

0.537

AC:

2584

AN:

4808

European-Finnish (FIN)

AF:

0.561

AC:

5928

AN:

10570

Middle Eastern (MID)

AF:

0.599

AC:

176

AN:

294

European-Non Finnish (NFE)

AF:

0.600

AC:

40787

AN:

67962

Other (OTH)

AF:

0.584

AC:

1232

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1877

3755

5632

7510

9387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<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:

0.604

Hom.:

48326

Bravo

AF:

0.616

Asia WGS

AF:

0.480

AC:

1672

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.8

(source)

DANN

Benign

0.72

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over