chr3-38603713-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001099404.2(SCN5A):​c.1889C>A​(p.Thr630Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,356,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T630R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense, splice_region

Scores

2
6
13
Splicing: ADA: 0.02854
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.24

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: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.34614763).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.1889C>A p.Thr630Lys missense_variant, splice_region_variant Exon 12 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.1889C>A p.Thr630Lys missense_variant, splice_region_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.1889C>A p.Thr630Lys missense_variant, splice_region_variant Exon 12 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.1889C>A p.Thr630Lys missense_variant, splice_region_variant Exon 12 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000811
AC:
11
AN:
1356224
Hom.:
0
Cov.:
30
AF XY:
0.00000906
AC XY:
6
AN XY:
662148
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30236
American (AMR)
AF:
0.00
AC:
0
AN:
29416
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19846
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38704
South Asian (SAS)
AF:
0.00
AC:
0
AN:
67776
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48886
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5200
European-Non Finnish (NFE)
AF:
0.0000104
AC:
11
AN:
1060356
Other (OTH)
AF:
0.00
AC:
0
AN:
55804
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
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
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Aug 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 630 of the SCN5A protein (p.Thr630Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1782022). 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. 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. -

Cardiovascular phenotype Uncertain:1
Jun 29, 2020
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.T630K variant (also known as c.1889C>A), located in coding exon 11 of the SCN5A gene, results from a C to A substitution at nucleotide position 1889. The threonine at codon 630 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
CardioboostArm
Benign
0.0010
CardioboostCm
Benign
0.00051
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.64
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.71
.;T;T;T;T;T;T;.;T
M_CAP
Pathogenic
0.43
D
MetaRNN
Benign
0.35
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.72
D
MutationAssessor
Benign
0.14
.;N;.;.;.;N;.;.;.
PhyloP100
1.2
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.62
Sift
Benign
0.27
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.47
T;T;T;T;T;T;T;T;T
Polyphen
0.90
P;P;.;P;.;P;P;.;.
Vest4
0.40
MutPred
0.33
Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);Gain of ubiquitination at T630 (P = 6e-04);
MVP
0.77
MPC
0.87
ClinPred
0.66
D
GERP RS
4.1
Varity_R
0.16
gMVP
0.72
Mutation Taster
=20/80
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.029
dbscSNV1_RF
Benign
0.23
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: rs777061524; hg19: chr3-38645204; COSMIC: COSV61116703; API