chr3-38614063-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001099404.2(SCN5A):c.615T>G(p.Tyr205*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,578,296 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1B:1

Conservation

PhyloP100: 7.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38614063-A-C is Pathogenic according to our data. Variant chr3-38614063-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587531.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Pathogenic=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.615T>G	p.Tyr205*	stop_gained	Exon 6 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.612-229T>G		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.615T>G	p.Tyr205*	stop_gained	Exon 6 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.612-229T>G		intron_variant	Intron 5 of 27	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000533

AC:

AN:

1426082

Hom.:

Cov.:

AF XY:

0.0000494

AC XY:

AN XY:

708220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000689

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 1

Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atrial fibrillation, familial, 10

Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1E

Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SCN5A-related disorder

Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 3

Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Uncertain:1

Mar 08, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia

Benign:1

Nov 11, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

Vest4

0.91

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over