chr3-38606764-C-T

Position:

chr3-38606764-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001099404.2(SCN5A):c.1045G>A(p.Asp349Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6

Conservation

PhyloP100: 1.17

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1045G>A	p.Asp349Asn	missense_variant	9/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1045G>A	p.Asp349Asn	missense_variant	9/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1045G>A	p.Asp349Asn	missense_variant	9/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1045G>A	p.Asp349Asn	missense_variant	9/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248950

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000295

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the SCN5A protein (p.Asp349Asn). This variant is present in population databases (rs779687673, gnomAD 0.009%). This missense change has been observed in individuals with Brugada syndrome (PMID: 23200271, 24721456, 29709101, 31737537, 33221895, 36220970). ClinVar contains an entry for this variant (Variation ID: 229230). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2022	PS3_supporting, PS4_supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 16, 2016

The p.Asp349Asn variant in SCN5A has been identified in one Caucasian individual with Brugada syndrome and as a compound heterozygote in one individual with sic k sinus syndrome (Kodma 2013, Savastano 2013). It has been identified in 2/1156 4 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs779687673). Computational prediction tools and conservat ion analysis suggest that the p.Asp349Asn variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, the clinical significance of the p.Asp349Asn variant is uncertain. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

May 15, 2018

- -

Brugada syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Aug 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

CardioboostCm

Benign

0.028

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

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

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.46

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

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.85

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

MutationTaster

Benign

0.99

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.39

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

REVEL

Uncertain

0.44

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.10

B;D;.;B;.;D;D;.;.

Vest4

0.45

MutPred

0.59

Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);Loss of phosphorylation at Y352 (P = 0.0749);

MVP

0.78

MPC

1.1

ClinPred

0.66

GERP RS

4.7

Varity_R

0.18

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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