2-166073487-G-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate
The NM_001165963.4(SCN1A):c.135C>A(p.Asp45Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D45N) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
3
16
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -1.02
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 5 ACMG points.
PM1
In a region_of_interest Disordered (size 32) in uniprot entity SCN1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr2-166073489-C-T is described in Lovd as [Pathogenic].
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.08936575).
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.135C>A | p.Asp45Glu | missense_variant | Exon 4 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.135C>A | p.Asp45Glu | missense_variant | Exon 3 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.135C>A | p.Asp45Glu | missense_variant | Exon 1 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.1 | c.135C>A | p.Asp45Glu | missense_variant | Exon 1 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727240
GnomAD4 exome
AF:
AC:
4
AN:
1461880
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
727240
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;.;T;.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
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
Benign
T
MutationAssessor
Benign
.;.;.;N;N;.;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
.;.;.;N;.;.;N;.;N;N
REVEL
Uncertain
Sift
Benign
.;.;.;T;.;.;T;.;T;T
Sift4G
Benign
.;.;.;T;.;.;T;.;T;T
Polyphen
0.23
.;.;.;.;B;.;.;B;B;.
Vest4
0.14, 0.20, 0.24, 0.22
MutPred
Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);Gain of methylation at K41 (P = 0.1203);
MVP
0.85
MPC
0.63
ClinPred
T
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
No publications associated with this variant yet.