NM_001099404.2:c.4218G>A

Variant names:

• chr3-38560174-C-T
• rs41311123
• NM_001099404.2:c.4218G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001099404.2(SCN5A):​c.4218G>A​(p.Gly1406Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,512 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1406G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (6 hom., cov: 33)
  • Exomes 𝑓: 0.014 (189 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: -2.04
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-38560174-C-T is Benign according to our data. Variant chr3-38560174-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36761.
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00822 (1252/152292) while in subpopulation NFE AF = 0.0143 (974/68026). AF 95% confidence interval is 0.0136. There are 6 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. 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.4218G>A	p.Gly1406Gly	synonymous	Exon 23 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.4215G>A	p.Gly1405Gly	synonymous	Exon 23 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.4218G>A	p.Gly1406Gly	synonymous	Exon 23 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.4218G>A	p.Gly1406Gly	synonymous	Exon 23 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4215G>A	p.Gly1405Gly	synonymous	Exon 23 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.4218G>A	p.Gly1406Gly	synonymous	Exon 23 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152174 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00773 AC: 1919 AN: 248288 AF XY: 0.00777

Gnomad AFR exome AF: 0.00306

Gnomad AMR exome AF: 0.00262

Gnomad ASJ exome AF: 0.000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00674

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00697

GnomAD4 exome AF: 0.0136 AC: 19851 AN: 1461220 Hom.: 189 Cov.: 32 AF XY: 0.0131 AC XY: 9486 AN XY: 726838

African (AFR) AF: 0.00269 AC: 90 AN: 33466

American (AMR) AF: 0.00260 AC: 116 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00289 AC: 249 AN: 86110

European-Finnish (FIN) AF: 0.00639 AC: 341 AN: 53376

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0165 AC: 18332 AN: 1111654

Other (OTH) AF: 0.0110 AC: 664 AN: 60358

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152292 Hom.: 6 Cov.: 33 AF XY: 0.00768 AC XY: 572 AN XY: 74468

African (AFR) AF: 0.00296 AC: 123 AN: 41546

American (AMR) AF: 0.00372 AC: 57 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10618

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0143 AC: 974 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0119 Hom.: 6

Bravo AF: 0.00791

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Cardiomyopathy (2)
-	-	1	Brugada syndrome (1)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (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
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.9
DANN	Benign	0.63
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41311123; hg19: chr3-38601665;