3-38550365-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001099404.2(SCN5A):​c.6007G>C​(p.Asp2003His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,982 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2003N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

4
9
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.86

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: 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: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.42287466).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.6007G>C p.Asp2003His missense_variant Exon 28 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.6004G>C p.Asp2002His missense_variant Exon 28 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.6007G>C p.Asp2003His missense_variant Exon 28 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.6004G>C p.Asp2002His missense_variant Exon 28 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000144
AC:
2
AN:
1384982
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
678632
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31586
American (AMR)
AF:
0.00
AC:
0
AN:
36178
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21108
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38902
South Asian (SAS)
AF:
0.00
AC:
0
AN:
73656
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50558
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5030
European-Non Finnish (NFE)
AF:
0.00000187
AC:
2
AN:
1071004
Other (OTH)
AF:
0.00
AC:
0
AN:
56960
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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

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
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
CardioboostArm
Benign
0.0025
CardioboostCm
Benign
0.011
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.64
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.55
.;.;.;.;.;N;.;.;.
PhyloP100
2.9
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.8
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.56
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;B;D;.;.
Vest4
0.31
MutPred
0.23
.;.;Gain of glycosylation at P2005 (P = 0.0892);.;.;Gain of glycosylation at P2005 (P = 0.0892);.;.;.;
MVP
0.89
MPC
1.6
ClinPred
0.93
D
GERP RS
5.5
Varity_R
0.21
gMVP
0.53
Mutation Taster
=24/76
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: rs376697724; hg19: chr3-38591856; API