rs41315493

Variant names:

• chr3-38550521-C-A
• rs41315493
• NM_001099404.2:c.5851G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38550521-C-A
• chr3-38550521-C-G
• chr3-38550521-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198056.3(SCN5A):​c.5851G>T​(p.Val1951Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,611,666 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1951M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (46 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:28 O:1
• Conservation: PhyloP100: 0.927
• Publications: 52 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035488904).
• BP6: Variant 3-38550521-C-A is Benign according to our data. Variant chr3-38550521-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00409 (623/152342) while in subpopulation AMR AF = 0.0273 (418/15306). AF 95% confidence interval is 0.0251. There are 7 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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_001099404.2	MANE Plus Clinical	c.5851G>T	p.Val1951Leu	missense	Exon 28 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.5848G>T	p.Val1950Leu	missense	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.5851G>T	p.Val1951Leu	missense	Exon 28 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.5851G>T	p.Val1951Leu	missense	Exon 28 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.5848G>T	p.Val1950Leu	missense	Exon 28 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.5851G>T	p.Val1951Leu	missense	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 617 AN: 152224 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00662 AC: 1633 AN: 246710 AF XY: 0.00520

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00298

Gnomad FIN exome AF: 0.000561

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00178 AC: 2598 AN: 1459324 Hom.: 46 Cov.: 31 AF XY: 0.00158 AC XY: 1145 AN XY: 725558

African (AFR) AF: 0.00281 AC: 94 AN: 33444

American (AMR) AF: 0.0405 AC: 1806 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26008

East Asian (EAS) AF: 0.00305 AC: 121 AN: 39632

South Asian (SAS) AF: 0.00163 AC: 140 AN: 86090

European-Finnish (FIN) AF: 0.000881 AC: 47 AN: 53330

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.000204 AC: 226 AN: 1110256

Other (OTH) AF: 0.00257 AC: 155 AN: 60254

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152342 Hom.: 7 Cov.: 33 AF XY: 0.00423 AC XY: 315 AN XY: 74486

African (AFR) AF: 0.00349 AC: 145 AN: 41588

American (AMR) AF: 0.0273 AC: 418 AN: 15306

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

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00186 Hom.: 3

Bravo AF: 0.00595

ESP6500AA AF: 0.00457 AC: 19

ESP6500EA AF: 0.000596 AC: 5

ExAC AF: 0.00525 AC: 635

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	9	not specified (10)
-	-	5	not provided (6)
-	-	1	Atrial fibrillation;C1142166:Brugada syndrome (1)
-	-	1	Brugada syndrome (1)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1E (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 3 (1)
-	-	1	Long QT syndrome;C0878544:Cardiomyopathy (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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.98
DANN	Benign	0.85
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.93
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.24	N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.76		Loss of helix (P = 0.0558)
MVP		0.77
MPC		0.50
ClinPred		0.0027	T
GERP RS		-0.53
Varity_R		0.051
gMVP		0.18
Mutation Taster		=88/12	polymorphism

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: rs41315493; hg19: chr3-38592012;