rs752639991
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BP4
The NM_001165963.4(SCN1A):c.1882T>A(p.Ser628Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,980 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
1
5
7
Clinical Significance
Conservation
PhyloP100: 7.19
Genes affected
SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_001165963.4
PP2
?
Missense variant where missense usually causes diseases, SCN1A
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28349784).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1882T>A | p.Ser628Thr | missense_variant | 14/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.1882T>A | p.Ser628Thr | missense_variant | 14/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+7700A>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251348Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135856
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727242
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74296
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 22, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains; Missense variants in this gene are often considered pathogenic (HGMD) - |
Migraine, familial hemiplegic, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 628 of the SCN1A protein (p.Ser628Thr). This variant is present in population databases (rs752639991, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions and/or Dravet Syndrome (PMID: 34645491; Invitae). ClinVar contains an entry for this variant (Variation ID: 206777). 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 not expected to disrupt SCN1A protein function with a negative 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. - |
Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;.;T;.;.;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Polyphen
0.26, 0.0070
.;.;.;B;B;.;B;B;B;.
Vest4
0.51, 0.54, 0.54, 0.47
MutPred
0.17
.;Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);Loss of phosphorylation at T625 (P = 0.112);
MVP
0.89
MPC
0.66
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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