rs780330020
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2
The NM_001040142.2(SCN2A):c.3670G>T(p.Ala1224Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
SCN2A
NM_001040142.2 missense
NM_001040142.2 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 9.81
Genes affected
SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854
BP6
Variant 2-165367366-G-T is Benign according to our data. Variant chr2-165367366-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206989.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 45 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.3670G>T | p.Ala1224Ser | missense_variant | 19/27 | ENST00000375437.7 | NP_001035232.1 | |
SCN2A | NM_001371246.1 | c.3670G>T | p.Ala1224Ser | missense_variant | 19/27 | ENST00000631182.3 | NP_001358175.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.3670G>T | p.Ala1224Ser | missense_variant | 19/27 | 5 | NM_001040142.2 | ENSP00000364586.2 | ||
SCN2A | ENST00000631182.3 | c.3670G>T | p.Ala1224Ser | missense_variant | 19/27 | 5 | NM_001371246.1 | ENSP00000486885.1 | ||
SCN2A | ENST00000283256.10 | c.3670G>T | p.Ala1224Ser | missense_variant | 19/27 | 1 | ENSP00000283256.6 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251328Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135844
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727208
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1224 of the SCN2A protein (p.Ala1224Ser). This variant is present in population databases (rs780330020, gnomAD 0.006%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 30564305). ClinVar contains an entry for this variant (Variation ID: 206989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. 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 | clinical testing | GeneDx | Oct 15, 2014 | p.Ala1224Ser (A1224S) GCT>TCT: c.3670 G>T in exon 19 of the SCN2A gene (NM_021007.2). The A1224S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1224S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, size, and/or other properties. This substitution alters a highly conserved residue in the predicted transmembrane segment S1 in the third homologous domain of the SCN2A protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported in association with SCN2A-related disorders. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2021 | 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
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T;.;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T;.;.;.;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.;L;L;L;L
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;.;.;.;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.;D;D
Sift4G
Uncertain
T;.;.;T;.;T;T
Polyphen
D;D;.;D;D;D;D
Vest4
MVP
ClinPred
D
GERP RS
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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