rs199473127

Positions:

chr3-38603885-G-C

Variant summary

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

The NM_001099404.2(SCN5A):c.1717C>G(p.Gln573Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.25

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.1717C>G	p.Gln573Glu	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1717C>G	p.Gln573Glu	missense_variant	12/28	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.1717C>G	p.Gln573Glu	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1717C>G	p.Gln573Glu	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.00000402

AC:

AN:

248994

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135070

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727118

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

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:

0.00000826

AC:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Congenital long QT 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 Long QT syndrome in the following publications (PMID:16414944). 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

0.087

CardioboostCm

Benign

0.0018

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

-0.0090

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.70

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

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.85

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.56

Sift

Benign

0.49

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

Sift4G

Benign

0.58

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

Polyphen

0.041

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

Vest4

0.81

MutPred

0.76

Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);Gain of phosphorylation at T570 (P = 0.1622);

MVP

0.90

MPC

0.45

ClinPred

0.11

GERP RS

4.1

Varity_R

0.13

gMVP

0.75

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