rs45489099

Positions:

• chr3-38620968-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000335.5(SCN5A):​c.486C>T​(p.Tyr162Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,613,890 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 3.41

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-38620968-G-A is Benign according to our data. Variant chr3-38620968-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=10}. Variant chr3-38620968-G-A is described in Lovd as [Benign]. Variant chr3-38620968-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.486C>T	p.Tyr162Tyr	synonymous_variant	5/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.486C>T	p.Tyr162Tyr	synonymous_variant	5/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.486C>T	p.Tyr162Tyr	synonymous_variant	5/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.486C>T	p.Tyr162Tyr	synonymous_variant	5/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152228 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000623 AC: 155 AN: 248802 Hom.: 0 AF XY: 0.000563 AC XY: 76 AN XY: 135034

Gnomad AFR exome AF: 0.00958

Gnomad AMR exome AF: 0.000174

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: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000266 AC: 389 AN: 1461544 Hom.: 1 Cov.: 32 AF XY: 0.000224 AC XY: 163 AN XY: 727030

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00241 AC: 367 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74504

Gnomad4 AFR AF: 0.00866

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.00312

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2019	Variant summary: SCN5A c.486C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 248802 control chromosomes. The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.486C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile) at our laboratory providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Tyr162Tyr in Exon 05 of SCN5A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 0.9% (28/3212) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45489099). -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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. -

Dilated cardiomyopathy 1E Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

Sick sinus syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Progressive familial heart block, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2016

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. -

Long QT syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 23, 2019

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.3
DANN	Benign	0.68

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

Other links and lift over

dbSNP: rs45489099; hg19: chr3-38662459;