NM_001099404.2:c.392+34C>A

Variant names:

• chr3-38630277-G-T
• rs41312963
• NM_001099404.2:c.392+34C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099404.2(SCN5A):​c.392+34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,426,582 control chromosomes in the GnomAD database, including 1,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (188 hom., cov: 33)
  • Exomes 𝑓: 0.036 (948 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.484
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-38630277-G-T is Benign according to our data. Variant chr3-38630277-G-T is described in ClinVar as Benign. ClinVar VariationId is 257440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.392+34C>A		intron_variant	Intron 3 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.392+34C>A		intron_variant	Intron 3 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.392+34C>A		intron_variant	Intron 3 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.392+34C>A		intron_variant	Intron 3 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6950 AN: 152182 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0341 AC: 8484 AN: 248620 AF XY: 0.0350

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0356 AC: 45310 AN: 1274282 Hom.: 948 Cov.: 19 AF XY: 0.0362 AC XY: 23324 AN XY: 643748

African (AFR) AF: 0.0826 AC: 2453 AN: 29710

American (AMR) AF: 0.0189 AC: 842 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1245 AN: 24878

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38828

South Asian (SAS) AF: 0.0501 AC: 4130 AN: 82516

European-Finnish (FIN) AF: 0.0249 AC: 1325 AN: 53274

Middle Eastern (MID) AF: 0.0583 AC: 315 AN: 5400

European-Non Finnish (NFE) AF: 0.0348 AC: 32771 AN: 940832

Other (OTH) AF: 0.0409 AC: 2224 AN: 54352

GnomAD4 genome AF: 0.0457 AC: 6955 AN: 152300 Hom.: 188 Cov.: 33 AF XY: 0.0444 AC XY: 3306 AN XY: 74476

African (AFR) AF: 0.0804 AC: 3340 AN: 41550

American (AMR) AF: 0.0280 AC: 428 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0469 AC: 226 AN: 4820

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2342 AN: 68032

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0384 Hom.: 197

Bravo AF: 0.0476

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.86
CADD	Benign	4.7
DANN	Benign	0.55
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41312963; hg19: chr3-38671768;