chr3-38603826-G-C

Variant summary

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

The NM_001099404.2(SCN5A):​c.1776C>G​(p.Asn592Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,612,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N592S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

3
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.07

Publications

7 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: 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6
Variant 3-38603826-G-C is Benign according to our data. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068. Variant chr3-38603826-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 923068.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.1776C>G p.Asn592Lys missense_variant Exon 12 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.1776C>G p.Asn592Lys missense_variant Exon 12 of 28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkc.1776C>G p.Asn592Lys missense_variant Exon 12 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.1776C>G p.Asn592Lys missense_variant Exon 12 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
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:
0.000194
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:
0.0000323
AC:
8
AN:
247882
AF XY:
0.0000298
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000445
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1460140
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726136
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33448
American (AMR)
AF:
0.00
AC:
0
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26030
East Asian (EAS)
AF:
0.000151
AC:
6
AN:
39668
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86118
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53224
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1110904
Other (OTH)
AF:
0.00
AC:
0
AN:
60302
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41432
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000194
AC:
1
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 592 of the SCN5A protein (p.Asn592Lys). This variant is present in population databases (rs199473130, gnomAD 0.05%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 24463578). ClinVar contains an entry for this variant (Variation ID: 923068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24463578). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia Benign:1
Feb 18, 2025
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
CardioboostArm
Benign
0.00034
CardioboostCm
Benign
0.0021
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Uncertain
0.52
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.5
.;M;.;.;.;M;.;.;.
PhyloP100
4.1
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-2.5
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.82
Sift
Benign
0.044
D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.54
T;T;T;T;T;T;T;T;T
Polyphen
0.32
B;P;.;B;.;P;P;.;.
Vest4
0.62
MutPred
0.32
Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);Gain of ubiquitination at N592 (P = 0.0219);
MVP
0.82
MPC
0.66
ClinPred
0.28
T
GERP RS
4.1
Varity_R
0.18
gMVP
0.72
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs199473130; hg19: chr3-38645317; API