3-38614063-A-G

Variant names:

• chr3-38614063-A-G
• rs765669597
• NM_001099404.2:c.615T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001099404.2(SCN5A):​c.615T>C​(p.Tyr205Tyr) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,426,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.615T>C	p.Tyr205Tyr	synonymous	Exon 6 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.612-229T>C		intron	N/A	NP_000326.2
	SCN5A	NM_001099405.2		c.615T>C	p.Tyr205Tyr	synonymous	Exon 6 of 27	NP_001092875.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.615T>C	p.Tyr205Tyr	synonymous	Exon 6 of 28	ENSP00000410257.1
	SCN5A	ENST00000414099.6	TSL:1	c.615T>C	p.Tyr205Tyr	synonymous	Exon 5 of 26	ENSP00000398962.2
	SCN5A	ENST00000455624.6	TSL:1	c.615T>C	p.Tyr205Tyr	synonymous	Exon 5 of 27	ENSP00000399524.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1426082 Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2 AN XY: 708220

African (AFR) AF: 0.00 AC: 0 AN: 32980

American (AMR) AF: 0.00 AC: 0 AN: 41258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39070

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088086

Other (OTH) AF: 0.0000169 AC: 1 AN: 59132

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Benign	0.59
PhyloP100		7.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765669597; hg19: chr3-38655554;