rs145731678

chr3-38551308-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001099404.2(SCN5A):c.5064C>T(p.Ile1688=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,100 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0560

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-38551308-G-A is Benign according to our data. Variant chr3-38551308-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.056 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5064C>T	p.Ile1688=	synonymous_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5061C>T	p.Ile1687=	synonymous_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5064C>T	p.Ile1688=	synonymous_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5061C>T	p.Ile1687=	synonymous_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251490 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000439

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74394

Gnomad4 AFR AF: 0.0000722

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2016	p.Ile1688Ile in exon 28 of SCN5A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 4/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs145731678). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	1.0
Dann	Benign	0.72

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

Other links and lift over

dbSNP: rs145731678; hg19: chr3-38592799; COSMIC: COSV61131894; COSMIC: COSV61131894;