rs199473552

Variant names:

• chr3-38633205-C-T
• rs199473552
• NM_001099404.2:c.103G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_198056.3(SCN5A):​c.103G>A​(p.Gly35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict 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. G35C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3 O:1
• Conservation: PhyloP100: 0.520
• Publications: 12 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13819748).
• BP6: Variant 3-38633205-C-T is Benign according to our data. Variant chr3-38633205-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67628.

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.103G>A	p.Gly35Ser	missense	Exon 2 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.103G>A	p.Gly35Ser	missense	Exon 2 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.103G>A	p.Gly35Ser	missense	Exon 2 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.103G>A	p.Gly35Ser	missense	Exon 2 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.103G>A	p.Gly35Ser	missense	Exon 2 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.103G>A	p.Gly35Ser	missense	Exon 2 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000966 AC: 24 AN: 248566 AF XY: 0.000126

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461196 Hom.: 1 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 726902

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1111824

Other (OTH) AF: 0.0000829 AC: 5 AN: 60348

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Brugada syndrome (2)
-	-	1	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	1	-	SCN5A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
CardioboostArm	Benign	0.0000024
CardioboostCm	Benign	0.0015
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.5
DANN	Benign	0.85
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.090	N
PhyloP100		0.52
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.70
MPC		0.36
ClinPred		0.044	T
GERP RS		-0.15
PromoterAI		0.0092	Neutral
Varity_R		0.035
gMVP		0.43
Mutation Taster		=32/68	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: rs199473552; hg19: chr3-38674696; COSMIC: COSV60067103;