NM_001099404.2:c.*1537T>C

Variant names:

• chr3-38548784-A-G
• rs41315485
• NM_001099404.2:c.*1537T>C

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.*1537T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,586 control chromosomes in the GnomAD database, including 3,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3531 hom., cov: 33)
  • Exomes 𝑓: 0.32 (23 hom.)
• Consequence: SCN5A NM_001099404.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.76
• Publications: 8 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=-0.96).
• BP6: Variant 3-38548784-A-G is Benign according to our data. Variant chr3-38548784-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. 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.*1537T>C		3_prime_UTR	Exon 28 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.*1537T>C		3_prime_UTR	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.*1537T>C		3_prime_UTR	Exon 28 of 28	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.*1537T>C		3_prime_UTR	Exon 28 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.*1537T>C		3_prime_UTR	Exon 28 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.*1537T>C		3_prime_UTR	Exon 28 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32396 AN: 152066 Hom.: 3527 Cov.: 33

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.321 AC: 129 AN: 402 Hom.: 23 Cov.: 0 AF XY: 0.307 AC XY: 75 AN XY: 244

African (AFR) AF: 0.125 AC: 1 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 2 AN: 4

European-Finnish (FIN) AF: 0.332 AC: 119 AN: 358

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.231 AC: 6 AN: 26

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.213 AC: 32416 AN: 152184 Hom.: 3531 Cov.: 33 AF XY: 0.213 AC XY: 15821 AN XY: 74392

African (AFR) AF: 0.184 AC: 7633 AN: 41538

American (AMR) AF: 0.188 AC: 2877 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3466

East Asian (EAS) AF: 0.101 AC: 523 AN: 5158

South Asian (SAS) AF: 0.169 AC: 817 AN: 4822

European-Finnish (FIN) AF: 0.283 AC: 3000 AN: 10590

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15943 AN: 67994

Other (OTH) AF: 0.206 AC: 436 AN: 2114

Alfa AF: 0.227 Hom.: 2447

Bravo AF: 0.208

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	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	-0.96
CADD	Benign	11
DANN	Benign	0.43
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41315485; hg19: chr3-38590275;