3-38550387-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001099404.2(SCN5A):c.5985C>A(p.Tyr1995*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.271

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0109 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein
SCN5A	NM_001099404.2	MANE Plus Clinical	c.5985C>A	p.Tyr1995*	stop_gained	Exon 28 of 28	NP_001092874.1
SCN5A	NM_000335.5	MANE Select	c.5982C>A	p.Tyr1994*	stop_gained	Exon 28 of 28	NP_000326.2
SCN5A	NM_198056.3		c.5985C>A	p.Tyr1995*	stop_gained	Exon 28 of 28	NP_932173.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.5985C>A	p.Tyr1995*	stop_gained	Exon 28 of 28	ENSP00000410257.1
SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.5982C>A	p.Tyr1994*	stop_gained	Exon 28 of 28	ENSP00000398266.2
SCN5A	ENST00000333535.9	TSL:1	c.5985C>A	p.Tyr1995*	stop_gained	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000484

AC:

AN:

206774

AF XY:

0.00000913

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000339

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402882

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32288

American (AMR)

AF:

0.0000255

AC:

AN:

39166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22122

East Asian (EAS)

AF:

0.00

AC:

AN:

39142

South Asian (SAS)

AF:

0.00

AC:

AN:

75966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079880

Other (OTH)

AF:

0.00

AC:

AN:

57796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 582303). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Tyr1995*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the SCN5A protein.

Congenital long QT syndrome

Uncertain:1

Oct 29, 2022

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y1995* variant (also known as c.5985C>A), located in coding exon 27 of the SCN5A gene, results from a C to A substitution at nucleotide position 5985. This changes the amino acid from a tyrosine to a stop codon within coding exon 27. This alteration occurs at the 3' terminus of theSCN5A gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 1% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.76

PhyloP100

-0.27

Vest4

0.78

GERP RS

2.2

Mutation Taster

=75/125

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over