chr3-38633228-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1PM2PP2BP4_ModerateBP6BS1

The NM_000335.5(SCN5A):c.80G>A(p.Arg27His) variant causes a missense change. The variant allele was found at a frequency of 0.0000762 in 1,613,204 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).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:8O:1

Conservation

PhyloP100: 4.16

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.

PM1

In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.264).

BP6

Variant 3-38633228-C-T is Benign according to our data. Variant chr3-38633228-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68043.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, not_provided=1}. Variant chr3-38633228-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152236) while in subpopulation AMR AF= 0.00105 (16/15302). AF 95% confidence interval is 0.000656. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.80G>A	p.Arg27His	missense_variant	Exon 2 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.80G>A	p.Arg27His	missense_variant	Exon 2 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.80G>A	p.Arg27His	missense_variant	Exon 2 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.80G>A	p.Arg27His	missense_variant	Exon 2 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000245

AC:

AN:

248780

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1460968

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00157

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:

0.0000153

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000164

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000276

ExAC

AF:

0.000232

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Nov 14, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies in mammalian cells showed that R27H causes a shift in mid-activation potential and slower channel inactivation at a less depolarized membrane potential, however R27H behaved similarly to wild type when expressed in frog oocytes (Gutter et al., 2013).; This variant is associated with the following publications: (PMID: 19716085, 23805106, 22984773, 26538325, 22840528, 11901046, 29247119, 27435932, 29728395, 30662450, 30291343) -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 29, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

update: reclassified variant to likely benign because of presence in 0.2% of alleles from Latinos in ExAC. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brugada syndrome 1

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia

Benign:2

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Death in infancy

Pathogenic:1

Mar 27, 2015

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 30, 2021

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. -

Congenital long QT syndrome

Other:1

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 as associated with Long QT syndrome in the following publications (PMID:11901046;PMID:19716085). 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

0.12

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

0.000092

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

.;.;.;.;.;D;.;.;.;T;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.26

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

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.4

.;M;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.11

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

Polyphen

0.99

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

Vest4

0.84

MVP

0.96

MPC

1.2

ClinPred

0.21

GERP RS

3.6

Varity_R

0.45

gMVP

0.62

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