3-38605953-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_000335.5(SCN5A):c.1336G>A(p.Glu446Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,602,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E446D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

SCN5A
NM_000335.5 missense, splice_region

Scores

Splicing: ADA: 0.9714

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:10O:1

Conservation

PhyloP100: 2.44

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 3-38605953-C-T is Benign according to our data. Variant chr3-38605953-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67656.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Likely_benign=7, Benign=3}. Variant chr3-38605953-C-T is described in Lovd as [Likely_benign]. Variant chr3-38605953-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000151 (23/152296) while in subpopulation SAS AF = 0.00269 (13/4828). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1336G>A	p.Glu446Lys	missense_variant, splice_region_variant	Exon 10 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1336G>A	p.Glu446Lys	missense_variant, splice_region_variant	Exon 10 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.1336G>A	p.Glu446Lys	missense_variant, splice_region_variant	Exon 10 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1336G>A	p.Glu446Lys	missense_variant, splice_region_variant	Exon 10 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000629

AC:

152

AN:

241774

AF XY:

0.000841

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00354

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000820

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000306

AC:

443

AN:

1449930

Hom.:

Cov.:

AF XY:

0.000396

AC XY:

285

AN XY:

719752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33148

American (AMR)

AF:

0.0000227

AC:

AN:

43998

Ashkenazi Jewish (ASJ)

AF:

0.00354

AC:

AN:

25432

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39568

South Asian (SAS)

AF:

0.00340

AC:

287

AN:

84418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000389

AC:

AN:

1104748

Other (OTH)

AF:

0.000351

AC:

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000151

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000744

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Uncertain:3Other:1

Genetics and Genomics Program, Sidra Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:21596231). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Brugada syndrome 1

Uncertain:2Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2019

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:2

Dec 16, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided

Benign:2

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN5A: BS1, BS2 -

Ventricular fibrillation, paroxysmal familial, type 1

Uncertain:1

Jan 31, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1E

Benign:1

Jan 31, 2019

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sick sinus syndrome 1

Benign:1

Jan 31, 2019

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Progressive familial heart block, type 1A

Benign:1

Jan 31, 2019

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

May 09, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Cardiac arrhythmia

Benign:1

Oct 20, 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

AlphaMissense

Benign

0.19

CardioboostArm

Benign

0.00041

CardioboostCm

Uncertain

0.20

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

.;.;.;.;.;D;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.065

T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

.;L;.;.;.;L;.;.;.

PhyloP100

2.4

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.093

T;T;T;T;T;T;T;T;T

Polyphen

0.99

D;D;.;D;.;D;D;.;.

Vest4

0.91

MVP

0.99

MPC

1.2

ClinPred

0.10

GERP RS

5.5

Varity_R

0.59

gMVP

0.81

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.78

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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3-38605953-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over