chr2-166037862-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate
The NM_001165963.4(SCN1A):c.2860G>A(p.Glu954Lys) variant causes a missense change involving the alteration of a 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.90
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_pathogenic. Variant got 9 ACMG points.
PM1
In a intramembrane_region Pore-forming (size 20) in uniprot entity SCN1A_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
PM2
Very rare variant in population databases, with high coverage;
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 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926
PP5
Variant 2-166037862-C-T is Pathogenic according to our data. Variant chr2-166037862-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68606.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.2860G>A | p.Glu954Lys | missense_variant | 18/29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.2860G>A | p.Glu954Lys | missense_variant | 17/28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.2827G>A | p.Glu943Lys | missense_variant | 15/26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.2776G>A | p.Glu926Lys | missense_variant | 15/26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 10, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 954 of the SCN1A protein (p.Glu954Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with classic Dravet syndrome or severe myoclonic epilepsy of infancy (PMID: 20110217, 21248271). ClinVar contains an entry for this variant (Variation ID: 68606). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Glu954 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Severe myoclonic epilepsy in infancy Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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
.;.;.;M;.;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;D;.;.;D;.;D;D
Sift4G
Uncertain
.;.;.;D;.;.;D;.;D;D
Polyphen
1.0, 0.18
.;.;.;D;B;.;D;B;B;.
Vest4
0.89, 0.90, 0.92, 0.91
MutPred
0.70
.;Loss of helix (P = 0.0041);.;Loss of helix (P = 0.0041);.;.;Loss of helix (P = 0.0041);.;.;.;
MVP
0.98
MPC
2.5
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