rs41313031

Variant names:

• chr3-38562456-G-A
• rs41313031
• NM_001099404.2:c.3922C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

The NM_000335.5(SCN5A):​c.3919C>T​(p.Leu1307Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,613,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1307L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 3.17
• Publications: 19 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: Orphanet, ClinGen
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp, G2P, Ambry Genetics
• 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), G2P, Ambry Genetics
• 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: AR, AD 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: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000335.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.030645698).
• BP6: Variant 3-38562456-G-A is Benign according to our data. Variant chr3-38562456-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 67836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00132 (201/152336) while in subpopulation AFR AF = 0.00467 (194/41586). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.3922C>T	p.Leu1308Phe	missense	Exon 22 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.3919C>T	p.Leu1307Phe	missense	Exon 22 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3922C>T	p.Leu1308Phe	missense	Exon 22 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.3922C>T	p.Leu1308Phe	missense	Exon 22 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3919C>T	p.Leu1307Phe	missense	Exon 22 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.3922C>T	p.Leu1308Phe	missense	Exon 22 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000340 AC: 84 AN: 246854 AF XY: 0.000269

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 214 AN: 1460874 Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 726624

African (AFR) AF: 0.00568 AC: 190 AN: 33472

American (AMR) AF: 0.000179 AC: 8 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111588

Other (OTH) AF: 0.000232 AC: 14 AN: 60330

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74490

African (AFR) AF: 0.00467 AC: 194 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.00133

ESP6500AA AF: 0.00404 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000454 AC: 55

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Brugada syndrome, lidocaine-induced (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostArm	Benign	0.0022
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.059
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.031	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.85
MVP		0.94
MPC		1.5
ClinPred		0.059	T
GERP RS		3.2
Varity_R		0.46
gMVP		0.97
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

Other links and lift over

dbSNP: rs41313031; hg19: chr3-38603947;