3-38598927-C-T

Position:

chr3-38598927-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001099404.2(SCN5A):c.2014G>A(p.Ala672Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,613,816 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 9 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6O:1

Conservation

PhyloP100: 2.42

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 Benign. Variant got -8 ACMG points.

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=0.008682013).

BP6

Variant 3-38598927-C-T is Benign according to our data. Variant chr3-38598927-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67704.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, not_provided=1, Uncertain_significance=1}. Variant chr3-38598927-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.2014G>A	p.Ala672Thr	missense_variant	13/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.2014G>A	p.Ala672Thr	missense_variant	13/28	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.2014G>A	p.Ala672Thr	missense_variant	13/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.2014G>A	p.Ala672Thr	missense_variant	13/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000795

AC:

198

AN:

248926

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

134956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000410

AC:

599

AN:

1461534

Hom.:

Cov.:

AF XY:

0.000630

AC XY:

458

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00645

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000236

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00685

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000281

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The SCN5A c.2014G>A (p.Ala672Thr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 111/140944 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.005815 (96/16510). This frequency is about 58 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been reported in the literature, mostly in controls, and without strong evidence for causality. In addition, one clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as likely benign. -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19841300;PMID:20129283). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2019	This variant is associated with the following publications: (PMID: 20129283, 19841300, 25351510) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 14, 2011

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala672Thr (A672T; c.2014 G>A) in the SCN5A gene This variant has not previously been reported in any individuals with LQTS or Brugada syndrome. It has, however, been seen in controls of 3 different ancestries. In total this variant has been seen in 3 out of ~8800 individuals from published controls and publicly available population datasets. In terms of Caucasian controls ethnically-matched to our patient, it has been seen in 1 out of ~5328 individuals. Kapa et al. from Ackerman’s group (2009; also Kapplinger et al. 2010) found the variant in 1 control individual of Asian ancestry out of ~1300 mixed-race controls (649 of which were Caucasian). This same paper reports that 3% of controls were positive for a variant in SCN5A. This variant is also present in 1 European American individual in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). It is present in dbSNP as rs199473140, and the source of this is 1 individual of Mexican ancestry in 1000 Genomes. (1000 Genomes contains 1092 individuals, 379 of which are of European ancestry.) GeneDx did not report controls. Variation at a nearby residues (plus or minus 10 amino acids) has been associated with disease, suggesting the possible functional importance of this region of the protein: L673P (LQT3) is in HGMD according to GeneDx; other variants include R680H (associated with SIDS; also with increased sodium current in vitro, but only under conditions of internal acidosis) and H681P (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database, citing Arnestad et al. 2007 and Priori et al. 2002). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar, hydrophobic alanine with a polar, hydrophilic threonine. The alanine at this location is not highly conserved among vertebrates; in fact, the reference amino acid is a threonine in 6 species of fish. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.005. SIFT predicts it to be “tolerated” with a score of 1. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

SCN5A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

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. -

Cardiac arrhythmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

CardioboostCm

Benign

0.0013

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Benign

0.40

DEOGEN2

Benign

0.34

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

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.84

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

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.0087

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

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

0.67

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

MutationTaster

Benign

0.83

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

PrimateAI

Benign

0.46

PROVEAN

Benign

1.5

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

REVEL

Uncertain

0.29

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

0.0020

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

Vest4

0.27

MVP

0.68

MPC

0.34

ClinPred

0.027

GERP RS

4.1

Varity_R

0.068

gMVP

0.74

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