rs45592631

Variant names:

• chr3-38548175-T-TCCCTCCTTTTTCCTACTCTCTTCTC
• rs45592631
• NM_001099404.2:c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG

Your query was ambiguous. Multiple possible variants found:

• chr3-38548175-T-TCCCTCCTTTTTCCTACTCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTCCTACCCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTCCTAGTCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTCCTATTCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTCCTCCTCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTCCTTCTCTCTTCTC
• chr3-38548175-T-TCCCTCCTTTTTTCTACTCTCTTCTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000335.5(SCN5A):​c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.99 (74187 hom., cov: 0)
  • Exomes 𝑓: 1.0 (2 hom.)
• Consequence: SCN5A NM_000335.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:7
• Conservation: PhyloP100: 0.612
• Publications: 7 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 -10 ACMG points.

• BP6: Variant 3-38548175-T-TCCCTCCTTTTTCCTACTCTCTTCTC is Benign according to our data. Variant chr3-38548175-T-TCCCTCCTTTTTCCTACTCTCTTCTC is described in ClinVar as Likely_benign. ClinVar VariationId is 345061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

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.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 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.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.*2145_*2146insGAGAAGAGAGTAGGAAAAAGGAGGG		3_prime_UTR	Exon 28 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150077 AN: 151932 Hom.: 74128 Cov.: 0

Gnomad AFR AF: 0.997

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.979

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.987

GnomAD4 exome AF: 1.00 AC: 4 AN: 4 Hom.: 2 Cov.: 0 AF XY: 1.00 AC XY: 4 AN XY: 4

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.988 AC: 150195 AN: 152050 Hom.: 74187 Cov.: 0 AF XY: 0.988 AC XY: 73434 AN XY: 74308

African (AFR) AF: 0.997 AC: 41325 AN: 41464

American (AMR) AF: 0.988 AC: 15105 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3418 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5166

South Asian (SAS) AF: 0.997 AC: 4790 AN: 4804

European-Finnish (FIN) AF: 0.979 AC: 10349 AN: 10574

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66760 AN: 67982

Other (OTH) AF: 0.987 AC: 2076 AN: 2104

Alfa AF: 0.977 Hom.: 2152

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Long QT syndrome (1)
-	-	1	Paroxysmal familial ventricular fibrillation (1)
-	-	1	Progressive familial heart block (1)
-	-	1	Sick sinus syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs45592631; hg19: chr3-38589666; COSMIC: COSV61134839; COSMIC: COSV61134839;