Variant 3-38603887-G-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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=0.002438426).

BP6

Variant 3-38603887-G-T is Benign according to our data. Variant chr3-38603887-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 67683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603887-G-T is described in Lovd as [Pathogenic]. Variant chr3-38603887-G-T is described in Lovd as [Benign]. Variant chr3-38603887-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1715C>A	p.Ala572Asp	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1715C>A	p.Ala572Asp	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.1715C>A	p.Ala572Asp	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1715C>A	p.Ala572Asp	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

605

AN:

152206

Hom.:

7

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0363

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00491

AC:

1222

AN:

248994

Hom.:

22

AF XY:

0.00460

AC XY:

622

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0387

Gnomad NFE exome

AF:

0.00295

Gnomad OTH exome

AF:

0.00546

GnomAD4 exome

AF:

0.00339

AC:

4960

AN:

1461628

Hom.:

48

Cov.:

31

AF XY:

0.00322

AC XY:

2343

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0378

Gnomad4 NFE exome

AF:

0.00243

Gnomad4 OTH exome

AF:

0.00338

GnomAD4 genome

AF:

0.00397

AC:

605

AN:

152324

Hom.:

7

Cov.:

32

AF XY:

0.00526

AC XY:

392

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0363

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00195

Hom.:

1

Bravo

AF:

0.00119

TwinsUK

AF:

0.00108

AC:

4

ALSPAC

AF:

0.00130

AC:

5

ESP6500AA

AF:

0.000245

AC:

1

ESP6500EA

AF:

0.00239

AC:

20

ExAC

AF:

0.00429

AC:

519

EpiCase

AF:

0.00169

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN5A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 03, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2020	This variant is associated with the following publications: (PMID: 23008441, 22378279, 20403459, 12820704, 27243970, 27153395, 27287068, 27930701, 18452873, 28781330, 29672598, 29214556, 28988457, 29032884, 32880476) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2017	Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies show the variant could have a gain-of-function implication (Ortiz-Bonin_2016), an affect on recovery time (Albert_2008), or acts like wild type SCN5A, although in the context of a certain genotype such as the SCN5A polymorphism H588R moderate dysfunction was observed (Tester_2010). Overall, the authors indicate that the variant is not associated with the LQTS phenotype. This variant was found in 1486/279922 control chromosomes (23 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.038676 (997/25778). This frequency is about 387 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 European (Finnish) origin. Multiple publications have cited the variant of interest in affected individuals. One family reported by Paulussen_2003 found the variant to be in two unaffected family members, with the proband carrying the variant and another pathogenic KCNQ1 variant, V254M, while Ortiz-Bonnin_2016 reported an affected family member that did not carry the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, based on reports of co-occurrence with a pathogenic variant in another gene, lack of co-segregation with disease phenotype, and an unexpectedly high frequency in controls, this variant is classified as benign, although the possibility of a modifier effect in certain genetic backgrounds cannot be ruled out. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2015	p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs36210423) and was re ported at slightly lower frequencies in control cohorts across multiple studies investigating the genetic cause of LQTS and related clinical entities (Mank-Seym our 2006, Arnestad 2007, Albert 2008, Tester 2010). There is a possibility that the p.Ala572Asp variant may have a minor impact on protein function (Albert 2008 , Tester 2010, Koval 2012); however, these in vitro assays may not accurately re present biological function. Although a modifying role in disease cannot be full y excluded, this variant is likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ventricular fibrillation, paroxysmal familial, type 1

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 29, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Brugada syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiac arrest

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 29, 2014

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Aug 16, 2017

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 03, 2023

- -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 06, 2021

- -

Dilated cardiomyopathy 1E

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sick sinus syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Progressive familial heart block, type 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 29, 2014

- -

Long QT syndrome 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2015

This alteration is classified as 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

Mar 19, 2018

- -

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:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). 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

BayesDel_addAF

Benign

-0.28

T

BayesDel_noAF

Benign

-0.17

CADD

Benign

20

DANN

Benign

0.96

DEOGEN2

Uncertain

0.44

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.61

D

LIST_S2

Benign

0.52

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

MetaRNN

Benign

0.0024

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

MetaSVM

Benign

-0.37

T

MutationAssessor

Benign

1.3

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

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.32

T

PROVEAN

Benign

-0.35

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

REVEL

Benign

0.27

Sift

Benign

0.44

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

Sift4G

Benign

0.23

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

Polyphen

0.022

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

Vest4

0.38

MVP

0.48

MPC

0.64

ClinPred

0.015

T

GERP RS

3.2

Varity_R

0.098

gMVP

0.71

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.

3-38603887-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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