chr3-38581377-G-A

Variant names:

• chr3-38581377-G-A
• rs41260344
• NM_001099404.2:c.2788-6C>T

Variant summary

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

The NM_000335.5(SCN5A):​c.2788-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,578,788 control chromosomes in the GnomAD database, including 1,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (182 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1169 hom.)
• Consequence: SCN5A NM_000335.5 splice_region, intron
• Scores: Splicing: ADA: 0.00009660
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.276
• Publications: 6 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: Orphanet, ClinGen
• Brugada syndrome 1

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

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

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• progressive familial heart block, type 1A

  Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• sick sinus syndrome 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• 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
• congenital heart disease

  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=-0.76).
• BP6: Variant 3-38581377-G-A is Benign according to our data. Variant chr3-38581377-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000335.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.2788-6C>T		splice_region intron	N/A	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.2788-6C>T		splice_region intron	N/A	NP_000326.2
	SCN5A	NM_198056.3		c.2788-6C>T		splice_region intron	N/A	NP_932173.1	Q14524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.2788-6C>T		splice_region intron	N/A	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2788-6C>T		splice_region intron	N/A	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.2788-6C>T		splice_region intron	N/A	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6290 AN: 152032 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0326 AC: 7369 AN: 226216 AF XY: 0.0334

Gnomad AFR exome AF: 0.0532

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0384

Gnomad EAS exome AF: 0.000173

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0386

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0373 AC: 53256 AN: 1426638 Hom.: 1169 Cov.: 36 AF XY: 0.0376 AC XY: 26476 AN XY: 703888

African (AFR) AF: 0.0557 AC: 1815 AN: 32596

American (AMR) AF: 0.0187 AC: 787 AN: 42026

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 946 AN: 24500

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39056

South Asian (SAS) AF: 0.0352 AC: 2880 AN: 81812

European-Finnish (FIN) AF: 0.0299 AC: 1568 AN: 52506

Middle Eastern (MID) AF: 0.0587 AC: 330 AN: 5624

European-Non Finnish (NFE) AF: 0.0391 AC: 42591 AN: 1089770

Other (OTH) AF: 0.0398 AC: 2337 AN: 58748

GnomAD4 genome AF: 0.0414 AC: 6304 AN: 152150 Hom.: 182 Cov.: 32 AF XY: 0.0394 AC XY: 2932 AN XY: 74400

African (AFR) AF: 0.0554 AC: 2298 AN: 41504

American (AMR) AF: 0.0313 AC: 478 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4822

European-Finnish (FIN) AF: 0.0296 AC: 314 AN: 10598

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2639 AN: 67990

Other (OTH) AF: 0.0436 AC: 92 AN: 2110

Alfa AF: 0.0395 Hom.: 81

Bravo AF: 0.0418

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiac arrhythmia (2)
-	-	2	not provided (2)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Dilated cardiomyopathy 1E (1)
-	-	1	Long QT syndrome 3 (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Progressive familial heart block, type 1A (1)
-	-	1	Sick sinus syndrome 1 (1)
-	-	1	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.6
DANN	Benign	0.66
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs41260344; hg19: chr3-38622868; COSMIC: COSV104658849;