rs760669515
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004588.5(SCN2B):c.250C>T(p.Arg84Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,098 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R84H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 2 hom. )
Consequence
SCN2B
NM_004588.5 missense
NM_004588.5 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 4.20
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 -4 ACMG points.
BS2
?
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2B | NM_004588.5 | c.250C>T | p.Arg84Cys | missense_variant | 3/4 | ENST00000278947.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2B | ENST00000278947.6 | c.250C>T | p.Arg84Cys | missense_variant | 3/4 | 1 | NM_004588.5 | P1 | |
SCN2B | ENST00000665446.1 | n.486C>T | non_coding_transcript_exon_variant | 4/4 | |||||
SCN2B | ENST00000669850.1 | n.492C>T | non_coding_transcript_exon_variant | 3/4 | |||||
SCN2B | ENST00000658882.1 | c.*75C>T | 3_prime_UTR_variant, NMD_transcript_variant | 4/5 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251318Hom.: 1 AF XY: 0.0000589 AC XY: 8AN XY: 135878
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461746Hom.: 2 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727174
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74504
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Jun 04, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 408876). This variant has not been reported in the literature in individuals affected with SCN2B-related conditions. This variant is present in population databases (rs760669515, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 84 of the SCN2B protein (p.Arg84Cys). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2020 | The p.R84C variant (also known as c.250C>T), located in coding exon 3 of the SCN2B gene, results from a C to T substitution at nucleotide position 250. The arginine at codon 84 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected by whole exome sequencing in an individual with sudden cardiac arrest due to idiopathic ventricular fibrillation. This individual also carried missense alterations in ANK2 (c.9689C>T p.Thr3230Met), CTNNA3 (c.1853A>G p.His618Arg), and TCAP (c.145G>A p.Glu49Lys) (Song JS et al. J. Hum. Genet., 2017 Jun;62:615-620). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
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