rs199473044

Variant names:

• chr3-38633256-G-A
• rs199473044
• NM_001099404.2:c.52C>T
• SCN5A p.Arg18Trp

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_000335.5(SCN5A):​c.52C>T​(p.Arg18Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:6 O:1
• Conservation: PhyloP100: 3.50
• Publications: 13 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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), Ambry Genetics, G2P
• 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: AD, AR 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38248214).
• BP6: Variant 3-38633256-G-A is Benign according to our data. Variant chr3-38633256-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67978.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000919 (14/152302) while in subpopulation SAS AF = 0.00125 (6/4818). AF 95% confidence interval is 0.000542. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.52C>T	p.Arg18Trp	missense	Exon 2 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.52C>T	p.Arg18Trp	missense	Exon 2 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.52C>T	p.Arg18Trp	missense	Exon 2 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.52C>T	p.Arg18Trp	missense	Exon 2 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.52C>T	p.Arg18Trp	missense	Exon 2 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.52C>T	p.Arg18Trp	missense	Exon 2 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000270 AC: 67 AN: 248478 AF XY: 0.000378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000166 AC: 243 AN: 1460636 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 166 AN XY: 726658

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86244

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52446

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5720

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111828

Other (OTH) AF: 0.000199 AC: 12 AN: 60360

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74472

African (AFR) AF: 0.0000481 AC: 2 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (4)
-	1	1	Brugada syndrome 1 (2)
-	1	1	not specified (2)
-	1	-	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 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
AlphaMissense	Benign	0.14
CardioboostArm	Uncertain	0.13
CardioboostCm	Benign	0.040
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.059	T
PromoterAI		-0.028	Neutral
Varity_R		0.26
gMVP		0.64
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199473044;

hg19: chr3-38674747;

COSMIC: COSV60066899;

COSMIC: COSV60066899;