rs1464663200

Variant names:

• chr3-38580955-G-A
• rs1464663200
• NM_001099404.2:c.3204C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38580955-G-A
• chr3-38580955-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000335.5(SCN5A):​c.3204C>T​(p.Gly1068Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,606,958 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1068G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_000335.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.109
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 3-38580955-G-A is Benign according to our data. Variant chr3-38580955-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 463322.

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.3204C>T	p.Gly1068Gly	synonymous	Exon 17 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.3204C>T	p.Gly1068Gly	synonymous	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.3204C>T	p.Gly1068Gly	synonymous	Exon 17 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.3204C>T	p.Gly1068Gly	synonymous	Exon 17 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.3204C>T	p.Gly1068Gly	synonymous	Exon 17 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.3204C>T	p.Gly1068Gly	synonymous	Exon 17 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000809 AC: 2 AN: 247300 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454778 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 722146

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106450

Other (OTH) AF: 0.0000333 AC: 2 AN: 60032

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152180 Hom.: 1 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.48
PhyloP100		-0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1464663200; hg19: chr3-38622446;