Genetic Variant SCN5A:c.1140+98G>A (chr3-38606571-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000335.5(SCN5A):c.1140+98G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,409,404 control chromosomes in the GnomAD database, including 455,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49377 hom., cov: 34)

Exomes 𝑓: 0.80 ( 406052 hom. )

Consequence

SCN5A
NM_000335.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.102

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 3-38606571-C-T is Benign according to our data. Variant chr3-38606571-C-T is described in ClinVar as [Benign]. Clinvar id is 1292202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606571-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1140+98G>A		intron_variant	Intron 9 of 27	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1140+98G>A		intron_variant	Intron 9 of 27	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.1140+98G>A		intron_variant	Intron 9 of 27	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1140+98G>A		intron_variant	Intron 9 of 27	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122321

AN:

152094

Hom.:

49327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.766

Gnomad AMR

AF:

0.813

Gnomad ASJ

AF:

0.800

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.868

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.794

Gnomad OTH

AF:

0.811

GnomAD4 exome

AF:

0.803

AC:

1008948

AN:

1257192

Hom.:

406052

AF XY:

0.804

AC XY:

498733

AN XY:

620146

show subpopulations

Gnomad4 AFR exome

AF:

0.779

Gnomad4 AMR exome

AF:

0.839

Gnomad4 ASJ exome

AF:

0.798

Gnomad4 EAS exome

AF:

0.972

Gnomad4 SAS exome

AF:

0.865

Gnomad4 FIN exome

AF:

0.808

Gnomad4 NFE exome

AF:

0.791

Gnomad4 OTH exome

AF:

0.808

GnomAD4 genome

AF:

0.804

AC:

122429

AN:

152212

Hom.:

49377

Cov.:

AF XY:

0.809

AC XY:

60215

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.786

Gnomad4 AMR

AF:

0.813

Gnomad4 ASJ

AF:

0.800

Gnomad4 EAS

AF:

0.984

Gnomad4 SAS

AF:

0.868

Gnomad4 FIN

AF:

0.812

Gnomad4 NFE

AF:

0.794

Gnomad4 OTH

AF:

0.814

Alfa

AF:

0.796

Hom.:

67245

Bravo

AF:

0.800

Asia WGS

AF:

0.909

AC:

3159

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.1

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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