NM_001099404.2:c.1756_1761delGCCCTC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS1

The NM_001099404.2(SCN5A):c.1756_1761delGCCCTC(p.Ala586_Leu587del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,612,764 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

SCN5A
NM_001099404.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 2.43

Publications

0 publications found

Variant links:

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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001099404.2.

BP6

Variant 3-38603840-GGAGGGC-G is Benign according to our data. Variant chr3-38603840-GGAGGGC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48291.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000787 (115/1460468) while in subpopulation SAS AF = 0.00125 (108/86170). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAdExome4. There are 90 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN5A	NM_001099404.2	MANE Plus Clinical	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	NP_001092874.1	H9KVD2
SCN5A	NM_000335.5	MANE Select	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	NP_000326.2
SCN5A	NM_198056.3		c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	NP_932173.1	Q14524-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	ENSP00000410257.1	H9KVD2
SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	ENSP00000398266.2	Q14524-2
SCN5A	ENST00000333535.9	TSL:1	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000149

AC:

AN:

248138

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1460468

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00125

AC:

108

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111228

Other (OTH)

AF:

0.0000663

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Brugada syndrome 1 (1)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Sudden unexplained death (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=68/132

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over