2-166047699-A-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_001165963.4(SCN1A):c.1098T>A(p.Asp366Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D366H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 1.08
Publications
7 publications found
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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PM1
In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001165963.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-166047701-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 390594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.1098T>A | p.Asp366Glu | missense_variant | Exon 11 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.1098T>A | p.Asp366Glu | missense_variant | Exon 10 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.1098T>A | p.Asp366Glu | missense_variant | Exon 8 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.2 | c.1098T>A | p.Asp366Glu | missense_variant | Exon 10 of 28 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link
Submissions by phenotype
Severe myoclonic epilepsy in infancy Other:1
-
UniProtKB/Swiss-Prot
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;H;H;.;H;H;H;H
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;D;.;.;D;.;D;D
Sift4G
Pathogenic
.;.;.;D;.;.;D;.;D;D
Polyphen
0.99, 0.73
.;.;.;D;P;.;D;P;P;.
Vest4
0.97, 0.97
MutPred
Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);Gain of catalytic residue at D366 (P = 0.1534);
MVP
1.0
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.