rs372623225

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS1

The NM_000335.5(SCN5A):c.954C>T(p.Asn318Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,610,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.40

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 -15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 3-38608195-G-A is Benign according to our data. Variant chr3-38608195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 463360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38608195-G-A is described in Lovd as [Benign]. Variant chr3-38608195-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.4 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000178 (259/1458548) while in subpopulation SAS AF= 0.000975 (84/86196). AF 95% confidence interval is 0.000806. There are 0 homozygotes in gnomad4_exome. There are 151 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.954C>T	p.Asn318Asn	synonymous_variant	Exon 8 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.954C>T	p.Asn318Asn	synonymous_variant	Exon 8 of 28	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.954C>T	p.Asn318Asn	synonymous_variant	Exon 8 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.954C>T	p.Asn318Asn	synonymous_variant	Exon 8 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

249252

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135220

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000178

AC:

259

AN:

1458548

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

151

AN XY:

725858

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000975

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000144

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000529

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 14, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn318Asn in exon 8 of SCN5A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 8/16512 European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs372623225). -

Cardiac arrhythmia

Benign:2

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 16, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.28

DANN

Benign

0.57

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