3-38585708-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_001099404.2(SCN5A):c.2770G>A(p.Val924Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000756 in 1,467,564 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V924A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5O:1

Conservation

PhyloP100: 6.17

Publications

5 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3184267).

BP6

Variant 3-38585708-C-T is Benign according to our data. Variant chr3-38585708-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48295.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000658 (5/75990) while in subpopulation SAS AF = 0.00187 (4/2144). AF 95% confidence interval is 0.000637. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.2770G>A	p.Val924Ile	missense_variant	Exon 16 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.2770G>A	p.Val924Ile	missense_variant	Exon 16 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.2770G>A	p.Val924Ile	missense_variant	Exon 16 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.2770G>A	p.Val924Ile	missense_variant	Exon 16 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

75990

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:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000316

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

240272

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000762

AC:

106

AN:

1391574

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

690200

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32158

American (AMR)

AF:

0.00

AC:

AN:

42540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23880

East Asian (EAS)

AF:

0.00

AC:

AN:

35178

South Asian (SAS)

AF:

0.000991

AC:

AN:

83742

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

48358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

1064428

Other (OTH)

AF:

0.0000712

AC:

AN:

56162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

AF:

0.0000658

AC:

AN:

75990

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

36488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25272

American (AMR)

AF:

0.00

AC:

AN:

6760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1716

East Asian (EAS)

AF:

0.00

AC:

AN:

2466

South Asian (SAS)

AF:

0.00187

AC:

AN:

2144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.0000316

AC:

AN:

31636

Other (OTH)

AF:

0.00

AC:

AN:

1054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000515

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Nov 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SCN5A c.2770G>A (p.Val924Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 18/119070 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0009805 (15/15298). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, however these classifications predate the ExAC database, when information about the occurrence of the variant in the South Asian population was not available. Considering the prevalence of the variant in the South Asian population, it was classified as likely benign. -

Jan 14, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20129283, 19841300) -

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 in the following publications (PMID:19841300;PMID:20129283). -

not specified

Uncertain:1

Dec 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Val924Ile variant in SCN5A has been reported in 2/2600 individuals in a broa d, though clinically and racially unspecified control population (Kapa 2009, Kap plinger 2010). It has not been detected in large and broad European American and African American populations screened by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS) although it remains possible that it is common i n other populations. This variant is also listed in dbSNP without frequency dat a (dbSNP rs199473177). The affected amino acid is not completely conserved in ev olution with 1 species naturally carrying the variant. This raises the possibil ity that the change is milder or benign. Of note, the variant is located in a d omain that is believed to be enriched in variants that are present in controls a lthough this does not rule out a pathogenic role (Kapa2009). Additional informat ion is needed to determine clinical significance of this variant. -

Brugada syndrome;C1859062:Long QT syndrome 3

Uncertain:1

Aug 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ventricular tachycardia

Uncertain:1

May 07, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 21, 2024

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. -

Cardiac arrhythmia

Benign:1

Nov 24, 2019

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

0.23

CardioboostArm

Uncertain

0.22

CardioboostCm

Benign

0.0072

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

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

Eigen

Benign

-0.042

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.32

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

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

0.86

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

PhyloP100

6.2

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.82

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.16

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

Polyphen

0.010

B;B;.;B;.;B;B;.;.

Vest4

0.74

MutPred

0.55

Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.76

MPC

0.89

ClinPred

0.18

GERP RS

4.1

Varity_R

0.36

gMVP

0.83

Mutation Taster

=8/92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over