2-165992332-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001165963.4(SCN1A):c.4943G>A(p.Arg1648His) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1648C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.83
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]
SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
In a transmembrane_region Helical; Name=S4 of repeat IV (size 16) in uniprot entity SCN1A_HUMAN there are 10 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 chr2-165992333-G-A 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941
PP5
Variant 2-165992332-C-T is Pathogenic according to our data. Variant chr2-165992332-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165992332-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.4943G>A | p.Arg1648His | missense_variant | Exon 29 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.4943G>A | p.Arg1648His | missense_variant | Exon 28 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.4910G>A | p.Arg1637His | missense_variant | Exon 26 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.1 | c.4859G>A | p.Arg1620His | missense_variant | Exon 26 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251356Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135846
GnomAD3 exomes
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1
AN:
251356
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AC XY:
0
AN XY:
135846
Gnomad AFR exome
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GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe myoclonic epilepsy in infancy Other:2
| not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
| not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Autosomal dominant epilepsy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2019 | Variant summary: SCN1A c.4943G>A (p.Arg1648His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251356 control chromosomes (gnomAD). c.4943G>A has been published in the literature in multiple affected individuals with varying disease severity, ranging from one reported unaffected individual to several individuals with GEFS+, Dravet syndrome, and related seizure disorder phenotypes (Escayg_2000, Depienne_2009, Depienne_2010, Oates_2018, Snoeijen-Schouwenaars_2019). Most of these patients were reported in a large family, where the variant co-segregated with the disease (Escayg_2000). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating mildly reduced channel inactivation resulting in persistent inward sodium current with significantly accelerated recovery (e.g. Spampanato_2004, Alekov_2000, Lossin_2002). In addition, functional studies in mouse models suggested increased excitability of neurons in the central nervous system, resulting in increased seizure susceptibility (e.g. Hedrich_2014, Salgueiro-Pereira_2019). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 26, 2023 | ClinVar contains an entry for this variant (Variation ID: 12882). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 10742094, 20522430). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1648 of the SCN1A protein (p.Arg1648His). 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. Experimental studies have shown that this missense change affects SCN1A function (PMID: 12086636, 20100831). - |
Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2000 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2023 | Published functional studies demonstrate a damaging effect as this variant alters the function of the sodium channel with a defect in channel inactivation (Spampanato et al., 2001; Lossin et al., 2002; Martin et al. 2010); Additional functional studies in a mouse model demonstrate that R1648H causes an interneuron-specific defect in action potential which causes neuronal network hyperexcitability (Hedrich et al., 2014; Salgueiro-Pereira et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12086636, 27267376, 16380441, 20522430, 10486327, 14702334, 20100831, 23311867, 10742094, 25378155, 11118488, 11567038, 28717674, 26410685, 30525188, 33841294, 32090326, 30659983) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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;.;.;.
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
.;.;.;.;D;.;D;D;.
Vest4
0.86, 0.94, 0.92, 0.87
MutPred
0.72
.;.;.;Loss of methylation at R1648 (P = 0.0359);.;Loss of methylation at R1648 (P = 0.0359);.;.;.;
MVP
1.0
MPC
2.0
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