NM_001099404.2:c.4300-14T>C

Variant names:

• chr3-38556592-A-G
• rs56104887
• NM_001099404.2:c.4300-14T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001099404.2(SCN5A):​c.4300-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,606,882 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:13
• Conservation: PhyloP100: 1.32
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-38556592-A-G is Benign according to our data. Variant chr3-38556592-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165139.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (168/152128) while in subpopulation NFE AF = 0.00157 (107/68008). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD,AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.4300-14T>C		intron	N/A	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.4297-14T>C		intron	N/A	NP_000326.2
	SCN5A	NM_198056.3		c.4300-14T>C		intron	N/A	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.4300-14T>C		intron	N/A	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4297-14T>C		intron	N/A	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.4300-14T>C		intron	N/A	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000879 AC: 216 AN: 245816 AF XY: 0.000796

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000939

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00135 AC: 1969 AN: 1454754 Hom.: 4 Cov.: 35 AF XY: 0.00129 AC XY: 930 AN XY: 722416

African (AFR) AF: 0.000180 AC: 6 AN: 33354

American (AMR) AF: 0.000225 AC: 10 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85364

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53222

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00165 AC: 1824 AN: 1107024

Other (OTH) AF: 0.00107 AC: 64 AN: 60064

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74358

African (AFR) AF: 0.000337 AC: 14 AN: 41496

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000567 AC: 6 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.00120

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Brugada syndrome 1 (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	-0.80
CADD	Benign	4.8
DANN	Benign	0.75
PhyloP100		1.3
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: rs56104887; hg19: chr3-38598083; COSMIC: COSV61126888; COSMIC: COSV61126888;