rs41276525

Variant names:

• chr3-38613799-G-A
• rs41276525
• NM_000335.5:c.647C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP6 BS1 BS2

The NM_198056.3(SCN5A):​c.647C>T​(p.Ser216Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,920 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:15 O:1
• Conservation: PhyloP100: 10.0
• Publications: 51 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 -7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_198056.3
• BP6: Variant 3-38613799-G-A is Benign according to our data. Variant chr3-38613799-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36767.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00067 (102/152338) while in subpopulation AMR AF = 0.00157 (24/15310). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 SD,AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_000335.5	MANE Select	c.647C>T	p.Ser216Leu	missense	Exon 6 of 28	NP_000326.2
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.703+176C>T		intron	N/A	NP_001092874.1
	SCN5A	NM_198056.3		c.647C>T	p.Ser216Leu	missense	Exon 6 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.647C>T	p.Ser216Leu	missense	Exon 6 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.647C>T	p.Ser216Leu	missense	Exon 6 of 28	ENSP00000328968.4
	SCN5A	ENST00000327956.7	TSL:1	c.647C>T	p.Ser216Leu	missense	Exon 6 of 28	ENSP00000333674.7

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000685 AC: 167 AN: 243886 AF XY: 0.000832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000648

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.00113 AC: 1641 AN: 1458582 Hom.: 3 Cov.: 30 AF XY: 0.00112 AC XY: 815 AN XY: 725232

African (AFR) AF: 0.000120 AC: 4 AN: 33420

American (AMR) AF: 0.000948 AC: 42 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 15 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.000749 AC: 64 AN: 85394

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53226

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00130 AC: 1447 AN: 1110520

Other (OTH) AF: 0.00101 AC: 61 AN: 60276

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000756

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.00130 AC: 11

ExAC AF: 0.000686 AC: 83

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	8	not provided (11)
-	1	2	not specified (3)
-	-	2	Cardiac arrhythmia (2)
-	1	1	Cardiovascular phenotype (2)
-	1	1	Dilated cardiomyopathy 1E (2)
-	2	-	Long QT syndrome 3 (2)
-	2	-	Sick sinus syndrome 1 (2)
-	1	-	Brugada syndrome (1)
-	1	-	Brugada syndrome 1 (1)
-	1	-	Progressive familial heart block, type 1A (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)
-	1	-	Ventricular fibrillation, paroxysmal familial, type 1 (1)
-	-	1	Ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostArm	Pathogenic	0.96
CardioboostCm	Benign	0.0082
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		10
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.96
MVP		0.99
ClinPred		0.23	T
GERP RS		4.3
Varity_R		0.92
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs41276525; hg19: chr3-38655290;