3-38579474-C-T

Variant names:

• chr3-38579474-C-T
• rs199473190
• NM_001099404.2:c.3250G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_198056.3(SCN5A):​c.3250G>A​(p.Gly1084Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,459,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1084R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: -0.520
• Publications: 14 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13329089).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198056.3. 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.3250G>A	p.Gly1084Ser	missense	Exon 18 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.3247G>A	p.Gly1083Ser	missense	Exon 18 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3250G>A	p.Gly1084Ser	missense	Exon 18 of 28	NP_932173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.3250G>A	p.Gly1084Ser	missense	Exon 18 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3247G>A	p.Gly1083Ser	missense	Exon 18 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.3250G>A	p.Gly1084Ser	missense	Exon 18 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000818 AC: 2 AN: 244388 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459260 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725820

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000672 AC: 3 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39674

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60276

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	not provided (1)
-	1	-	SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 (1)
-	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostArm	Benign	0.00041
CardioboostCm	Benign	0.0031
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	7.6
DANN	Benign	0.89
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.80	N
PhyloP100		-0.52
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.56
Sift	Benign	0.86	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.67
MVP		0.99
MPC		0.030
ClinPred		0.029	T
GERP RS		-0.91
Varity_R		0.044
gMVP		0.41
Mutation Taster		=2/98	disease causing

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: rs199473190; hg19: chr3-38620965; COSMIC: COSV100351049;