chr3-38630376-G-T

Position:

chr3-38630376-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_001099404.2(SCN5A):c.327C>A(p.Asn109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,844 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N109N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.108

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 4 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 24 pathogenic changes around while only 9 benign (73%) in NM_001099404.2

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.38602984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.327C>A	p.Asn109Lys	missense_variant	3/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.327C>A	p.Asn109Lys	missense_variant	3/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.327C>A	p.Asn109Lys	missense_variant	3/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.327C>A	p.Asn109Lys	missense_variant	3/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249520

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135334

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 10, 2023

This missense variant replaces asparagine with lysine at codon 109 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 19843921, 20129283, 21273195, 25904541, 32893267). This variant has been identified in 1/249520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Brugada syndrome

Other:1

not provided, no classification provided

literature only

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

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19843921;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Benign

0.0073

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

.;.;.;.;.;T;.;.;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.69

.;T;T;T;T;T;T;.;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.39

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

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

-0.27

.;N;.;.;.;N;.;.;.;.

MutationTaster

Benign

0.85

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

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.67

N;N;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.27

T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.87

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

Polyphen

0.21

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

Vest4

0.76

MutPred

0.85

Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);

MVP

0.70

MPC

0.40

ClinPred

0.17

GERP RS

-1.6

Varity_R

0.11

gMVP

0.66

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