rs121918282
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_001040151.2(SCN3B):c.29T>C(p.Leu10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00043 ( 0 hom. )
Consequence
SCN3B
NM_001040151.2 missense
NM_001040151.2 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 0.766
Genes affected
SCN3B (HGNC:20665): (sodium voltage-gated channel beta subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel beta subunit gene family, and influences the inactivation kinetics of the sodium channel. Two alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29861468).
BS2
?
High AC in GnomAd4 at 51 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN3B | NM_001040151.2 | c.29T>C | p.Leu10Pro | missense_variant | 2/7 | ENST00000299333.8 | |
LOC105369543 | XR_948124.4 | n.89A>G | non_coding_transcript_exon_variant | 1/3 | |||
SCN3B | NM_018400.4 | c.29T>C | p.Leu10Pro | missense_variant | 1/6 | ||
SCN3B | XM_011542897.3 | c.29T>C | p.Leu10Pro | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN3B | ENST00000299333.8 | c.29T>C | p.Leu10Pro | missense_variant | 2/7 | 1 | NM_001040151.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152210Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
51
AN:
152210
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251474Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135910
GnomAD3 exomes
AF:
AC:
51
AN:
251474
Hom.:
AF XY:
AC XY:
33
AN XY:
135910
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000434 AC: 635AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.000392 AC XY: 285AN XY: 727248
GnomAD4 exome
AF:
AC:
635
AN:
1461894
Hom.:
Cov.:
31
AF XY:
AC XY:
285
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74372
GnomAD4 genome
?
AF:
AC:
51
AN:
152210
Hom.:
Cov.:
33
AF XY:
AC XY:
19
AN XY:
74372
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
2
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
21
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:5Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Brugada syndrome 7 Pathogenic:2Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 10 of the SCN3B protein (p.Leu10Pro). This variant is present in population databases (rs121918282, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of SCN3B-related conditions (PMID: 20031595, 21051419, 22284586, 25650408, 25757662, 29247119, 31043699). ClinVar contains an entry for this variant (Variation ID: 2470). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN3B function (PMID: 20031595, 21051419, 23257389). 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. - |
Pathogenic, flagged submission | literature only | OMIM | Mar 01, 2011 | - - |
Likely pathogenic, flagged submission | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 24667784, 22284586, 25757662, 23414114, 24055113, 24144883, 26728597, 25668026, 20031595, 25650408, 21051419, 25691686, 20558140, 36362949, 34572065, 35083300, 31961030, 35385795, 35456365, LauK2016[Abstract], 32684122, 36354758, 34495297, 23257389, 34867379, 30821013, 31019283, 31043699, 29247119) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 28, 2021 | - - |
Atrial fibrillation, familial, 16 Pathogenic:1
Pathogenic, flagged submission | literature only | OMIM | Mar 01, 2011 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 23, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Leu10Pro vari ant in SCN3B has been reported in 1 individual with Brugada syndrome and 1 indiv idual with atrial fibrillation (Hu 2009, Olesen 2011, Olesen 2014). In addition, this variant has been identified in 19/66726 of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP 12191828 2). In vitro functional studies provide some evidence that this variant may impa ct protein function (Hu 2009, Olesen 201), though these types of assays may not accurately represent biological function. Leucine (Leu) at position 10 is not co nserved in mammals with 3 mammals (gibbon, hedgehog, and shrew) carrying a proli ne (Pro) at this position, raising the possibility that this change may be toler ated. In summary, although the clinical significance of the p.Leu10Pro variant is uncertain it is less likely disease causing. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;.;.
Polyphen
B;B;B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at