19-35033883-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_199037.5(SCN1B):​c.592A>G​(p.Ser198Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,600,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SCN1B
NM_199037.5 missense

Scores

2
14

Clinical Significance

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

Conservation

PhyloP100: -0.489
Variant links:
Genes affected
SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04218176).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000526 (8/152058) while in subpopulation AMR AF= 0.000458 (7/15270). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN1BNM_001037.5 linkc.448+144A>G intron_variant Intron 3 of 5 ENST00000262631.11 NP_001028.1 Q07699-1
SCN1BNM_199037.5 linkc.592A>G p.Ser198Gly missense_variant Exon 3 of 3 NP_950238.1 Q07699-2
SCN1BNM_001321605.2 linkc.349+144A>G intron_variant Intron 3 of 5 NP_001308534.1 Q07699A0A1W2PR05

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN1BENST00000262631.11 linkc.448+144A>G intron_variant Intron 3 of 5 1 NM_001037.5 ENSP00000262631.3 Q07699-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152058
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000495
AC:
11
AN:
222284
Hom.:
0
AF XY:
0.0000497
AC XY:
6
AN XY:
120676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000203
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000138
AC:
20
AN:
1447984
Hom.:
0
Cov.:
33
AF XY:
0.0000139
AC XY:
10
AN XY:
718852
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.000237
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000362
Gnomad4 OTH exome
AF:
0.0000835
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152058
Hom.:
0
Cov.:
31
AF XY:
0.0000808
AC XY:
6
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000567
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000166
AC:
2

ClinVar

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

Submissions by phenotype

Brugada syndrome 5 Uncertain:1
Nov 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 198 of the SCN1B protein (p.Ser198Gly). This variant is present in population databases (rs763402433, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 24981977). ClinVar contains an entry for this variant (Variation ID: 190864). 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. -

not provided Uncertain:1
Mar 29, 2014
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ser198Gly (AGC>GGC): c.592 A>G in exon 3 of the SCN1B gene (NM_199037.2). The S198G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S198G variant was not observed in approximately 3600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. One missense mutation in a nearby residue (Q204R) has been reported in association with Brugada syndrome. The S198G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs in an alternate transcript of the SCN1B protein at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Brugada syndrome is primarily an autosomal dominant disease characterized by ST segment elevation on ECG in the absence of structural heart disease, associated with increased risk for syncope, ventricular tachyarrhythmia and sudden cardiac death. Brugada syndrome is most frequently caused by mutations in the genes encoding cardiac ion channel proteins, which regulate sodium and calcium movement in and out of cardiac cells (Fowler S et al., 2008; Hedley P et al., 2009). Although rare, mutations in the SCN1B gene have been reported in association with Brugada syndrome (Brugada R et al., 2012). The variant is found in BRUGADA panel(s). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
2.1
DANN
Benign
0.84
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.26
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-0.78
T
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.1
N;.
REVEL
Benign
0.11
Sift
Benign
0.084
T;.
Sift4G
Uncertain
0.018
D;.
Polyphen
0.0010
B;.
Vest4
0.064
MutPred
0.17
Loss of sheet (P = 0.0037);.;
MVP
0.52
MPC
0.65
ClinPred
0.047
T
GERP RS
-1.3
gMVP
0.11

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763402433; hg19: chr19-35524787; API