rs780360360
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_001165963.4(SCN1A):c.4612G>A(p.Val1538Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,612,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 4.86
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 Likely_benign. Variant got -1 ACMG points.
PM1
In a repeat IV (size 298) in uniprot entity SCN1A_HUMAN there are 62 pathogenic changes around while only 3 benign (95%) in NM_001165963.4
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4612G>A | p.Val1538Ile | missense_variant | 28/29 | ENST00000674923.1 | NP_001159435.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4612G>A | p.Val1538Ile | missense_variant | 28/29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.4612G>A | p.Val1538Ile | missense_variant | 27/28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.4579G>A | p.Val1527Ile | missense_variant | 25/26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.4528G>A | p.Val1510Ile | missense_variant | 25/26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151876Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249908Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135040
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460756Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726662
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 151876Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74160
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SCN1A: PM1, PS4:Moderate, PM2:Supporting - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1538 of the SCN1A protein (p.Val1538Ile). This variant is present in population databases (rs780360360, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 18930999, 24066114; Invitae). ClinVar contains an entry for this variant (Variation ID: 496120). 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 SCN1A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2016 | The p.V1538I variant (also known as c.4612G>A), located in coding exon 25 of the SCN1A gene, results from a G to A substitution at nucleotide position 4612. The valine at codon 1538 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an individual with late onset Dravet syndrome and an individual with isolated autism spectrum disorder (ASD) (Depienne C et al. J. Med. Genet., 2009 Mar;46:183-91; Koshimizu E et al. PLoS ONE, 2013 Sep;8:e74167). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;T;.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;L;.;.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N;.;.;N;.;N;N
REVEL
Uncertain
Sift
Benign
.;.;.;D;.;.;D;.;D;D
Sift4G
Benign
.;.;.;T;.;.;T;.;T;T
Polyphen
1.0
.;.;.;.;D;.;.;D;D;.
Vest4
0.42, 0.39, 0.39, 0.42
MutPred
0.35
.;.;.;Gain of catalytic residue at V1538 (P = 0.1079);.;.;Gain of catalytic residue at V1538 (P = 0.1079);.;.;.;
MVP
0.96
MPC
1.5
ClinPred
T
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