rs200761835
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004588.5(SCN2B):c.118G>A(p.Val40Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
SCN2B
NM_004588.5 missense
NM_004588.5 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 4.28
Genes affected
SCN2B (HGNC:10589): (sodium voltage-gated channel beta subunit 2) The protein encoded by this gene is the beta 2 subunit of the type II voltage-gated sodium channel. The encoded protein is involved in cell-cell adhesion and cell migration. Defects in this gene can be a cause of Brugada Syndrome, atrial fibrillation, or sudden infant death syndrome. [provided by RefSeq, Jul 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18844536).
BS2
?
High AC in GnomAdExome4 at 114 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2B | NM_004588.5 | c.118G>A | p.Val40Ile | missense_variant | 2/4 | ENST00000278947.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2B | ENST00000278947.6 | c.118G>A | p.Val40Ile | missense_variant | 2/4 | 1 | NM_004588.5 | P1 | |
SCN2B | ENST00000665446.1 | n.354G>A | non_coding_transcript_exon_variant | 3/4 | |||||
SCN2B | ENST00000669850.1 | n.360G>A | non_coding_transcript_exon_variant | 2/4 | |||||
SCN2B | ENST00000658882.1 | c.222G>A | p.Thr74= | synonymous_variant, NMD_transcript_variant | 3/5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251472Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135918
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GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000811 AC XY: 59AN XY: 727244
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atrial fibrillation, familial, 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 40 of the SCN2B protein (p.Val40Ile). This variant is present in population databases (rs200761835, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 191494). 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 isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2021 | The p.V40I variant (also known as c.118G>A), located in coding exon 2 of the SCN2B gene, results from a G to A substitution at nucleotide position 118. The valine at codon 40 is replaced by isoleucine, an amino acid with highly similar properties. This variant co-occurred with variants in other cardiac-related genes in an individual from a Brugada syndrome cohort, and has been reported as a secondary cardiac variant in an exome cohort; however, details were limited (Di Resta C et al. Hum Mol Genet, 2015 Oct;24:5828-35; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at