NM_001099404.2:c.1890+50C>T

Variant names:

• chr3-38603662-G-A
• rs9827213
• NM_001099404.2:c.1890+50C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099404.2(SCN5A):​c.1890+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,488,466 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (17 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.108
• Publications: 1 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=-0.89).
• BP6: Variant 3-38603662-G-A is Benign according to our data. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603662-G-A is described in CliVar as Likely_benign. Clinvar id is 257438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00924 (1407/152302) while in subpopulation AFR AF = 0.0321 (1333/41578). AF 95% confidence interval is 0.0306. There are 28 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1890+50C>T		intron_variant	Intron 12 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1890+50C>T		intron_variant	Intron 12 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1890+50C>T		intron_variant	Intron 12 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1890+50C>T		intron_variant	Intron 12 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.00923 AC: 1404 AN: 152184 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00291 AC: 482 AN: 165830 AF XY: 0.00224

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000903 AC: 1207 AN: 1336164 Hom.: 17 Cov.: 30 AF XY: 0.000801 AC XY: 521 AN XY: 650602

African (AFR) AF: 0.0329 AC: 986 AN: 29928

American (AMR) AF: 0.00175 AC: 49 AN: 28058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19446

East Asian (EAS) AF: 0.00 AC: 0 AN: 38538

South Asian (SAS) AF: 0.0000478 AC: 3 AN: 62722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45184

Middle Eastern (MID) AF: 0.00321 AC: 14 AN: 4358

European-Non Finnish (NFE) AF: 0.0000389 AC: 41 AN: 1052882

Other (OTH) AF: 0.00207 AC: 114 AN: 55048

GnomAD4 genome AF: 0.00924 AC: 1407 AN: 152302 Hom.: 28 Cov.: 32 AF XY: 0.00896 AC XY: 667 AN XY: 74460

African (AFR) AF: 0.0321 AC: 1333 AN: 41578

American (AMR) AF: 0.00353 AC: 54 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00774 Hom.: 2

Bravo AF: 0.0104

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely 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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.89
CADD	Benign	4.5
DANN	Benign	0.49
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs9827213; hg19: chr3-38645153;