rs794726719
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001165963.4(SCN1A):c.675G>C(p.Lys225Asn) variant causes a missense change. 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
14
4
1
Clinical Significance
Conservation
PhyloP100: 6.27
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 Pathogenic. Variant got 15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 2-166052871-C-G is Pathogenic according to our data. Variant chr2-166052871-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 189871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.675G>C | p.Lys225Asn | missense_variant | 8/29 | ENST00000674923.1 | NP_001159435.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.675G>C | p.Lys225Asn | missense_variant | 8/29 | NM_001165963.4 | ENSP00000501589 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+16741C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2015 | The K225N missense variant in the SCN1A gene has been reported previously in association with Dravetsyndrome (Xu et al., 2013). This substitution alters a highly conserved position predicted to be within thetransmembrane segment S4 of the first homologous domain of the SCN1A protein, and many other missensevariants have been reported in this region of the protein in association with SCN1A-related disorders(SCN1A Variant Database). The K225N variant is a semi-conservative amino acid substitution, which mayimpact secondary protein structure as these residues differ in some properties, and in silico analysis predictsthis variant is probably damaging to the protein structure/function. Therefore, we interpret this variant as pathogenic. - |
Severe myoclonic epilepsy in infancy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Bioinformatics, Peking University | Dec 20, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;H;H;.;H;H;H;H
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;.;.;D;.;D;D
Sift4G
Pathogenic
.;.;D;.;.;D;.;D;D
Polyphen
1.0, 1.0
.;.;D;D;.;D;D;D;.
Vest4
0.97, 0.99, 0.98, 0.97
MutPred
Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);Loss of ubiquitination at K225 (P = 0.0255);
MVP
1.0
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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