Genetic Variant NM_001099404.2:c.1339-24G>A (chr3-38604932-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001099404.2(SCN5A):c.1339-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,592,430 control chromosomes in the GnomAD database, including 29,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2697 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27185 hom. )

Consequence

SCN5A
NM_001099404.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.846

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 3-38604932-C-T is Benign according to our data. Variant chr3-38604932-C-T is described in ClinVar as [Benign]. Clinvar id is 257437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38604932-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1339-24G>A		intron_variant	Intron 10 of 27	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1339-24G>A		intron_variant	Intron 10 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.1339-24G>A		intron_variant	Intron 10 of 27	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1339-24G>A		intron_variant	Intron 10 of 27	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28410

AN:

152030

Hom.:

2689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.0941

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.184

GnomAD3 exomes

AF:

0.186

AC:

39952

AN:

214270

Hom.:

3740

AF XY:

0.189

AC XY:

21839

AN XY:

115324

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.163

Gnomad EAS exome

AF:

0.0845

Gnomad SAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.193

AC:

277865

AN:

1440282

Hom.:

27185

Cov.:

AF XY:

0.194

AC XY:

138586

AN XY:

714172

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.196

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.0891

Gnomad4 SAS exome

AF:

0.205

Gnomad4 FIN exome

AF:

0.176

Gnomad4 NFE exome

AF:

0.198

Gnomad4 OTH exome

AF:

0.190

GnomAD4 genome

AF:

0.187

AC:

28452

AN:

152148

Hom.:

2697

Cov.:

AF XY:

0.189

AC XY:

14076

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.169

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.146

Gnomad4 EAS

AF:

0.0943

Gnomad4 SAS

AF:

0.214

Gnomad4 FIN

AF:

0.174

Gnomad4 NFE

AF:

0.206

Gnomad4 OTH

AF:

0.186

Alfa

AF:

0.196

Hom.:

1700

Bravo

AF:

0.186

Asia WGS

AF:

0.173

AC:

603

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.94

CADD

Benign

0.069

DANN

Benign

0.49

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

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