3-38581065-C-T

Position:

chr3-38581065-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBP6

The NM_001099404.2(SCN5A):c.3094G>A(p.Glu1032Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. E1032D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.96

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN5A

BP4

Computational evidence support a benign effect (MetaRNN=0.05863473).

BP6

Variant 3-38581065-C-T is Benign according to our data. Variant chr3-38581065-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201490.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.3094G>A	p.Glu1032Lys	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.3094G>A	p.Glu1032Lys	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.3094G>A	p.Glu1032Lys	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.3094G>A	p.Glu1032Lys	missense_variant	17/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

248578

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134928

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461654

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2012	The Glu1032Lys variant in the SCN5A gene has been reported previously in one patient with an unspecified arrhythmia (Oliva Sandoval MJ et al., 2011). Although Glu1032Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic Acid with a positively charged Lysine, this substitution occurs at a position that is not well conserved across species. Consequently, in silico analysis predicts Glu1032Lys has a benign effect on the protein structure/function. One nearby mutation (Gln1033Arg) has been reported in association with LQTS. The Glu1032Lys variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.With the clinical and molecular information available at this time, we cannot definitively determine if Glu1032Lys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1032 of the SCN5A protein (p.Glu1032Lys). This variant is present in population databases (rs369565476, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome and/or other SCN5A-related conditions (PMID: 26669661, 30847666). ClinVar contains an entry for this variant (Variation ID: 201490). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

CardioboostCm

Benign

0.0026

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.23

DANN

Benign

0.65

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.021

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.059

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

MetaSVM

Benign

-0.79

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.24

PROVEAN

Benign

0.0

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

REVEL

Uncertain

0.39

Sift

Benign

0.83

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

Sift4G

Benign

0.74

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

Polyphen

0.0

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

Vest4

0.13

MVP

0.78

MPC

0.031

ClinPred

0.012

GERP RS

-5.7

Varity_R

0.035

gMVP

0.56

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