rs794726726
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001165963.4(SCN1A):c.5536_5539delAAAC(p.Lys1846SerfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001165963.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.5536_5539delAAAC | p.Lys1846SerfsTer11 | frameshift_variant | Exon 29 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.5536_5539delAAAC | p.Lys1846SerfsTer11 | frameshift_variant | Exon 28 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.5503_5506delAAAC | p.Lys1835SerfsTer11 | frameshift_variant | Exon 26 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.1 | c.5452_5455delAAAC | p.Lys1818SerfsTer11 | frameshift_variant | Exon 26 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with Dravet syndrome, including individuals where the variant occurred de novo. -
Frameshift variant in the C-terminus predicted to result in protein truncation as the last 164 amino acids are lost and replaced with 10 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18930999, 31864146, 26096185, 32090326, 16458823, 17347258, 18413471, 11359211, 17054684, 14504318, 21719429, 30945278, 31765958, 31031587) -
SCN1A: PS2, PS4, PM2, PVS1:Moderate -
Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:2
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Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple premature termination variants downstream have been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has previously been described as pathogenic in multiple patients, including as de novo in patients with Dravet syndrome or infantile onset generalised tonic-clonic seizures (ClinVar, VCGS, PMIDs: 21719429, 29141279, 18413471). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Severe myoclonic epilepsy in infancy Pathogenic:2
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A heterozygous one-base pair deletion in exon 29 of the SCN1A gene (c.5536_5539delAAAC) that results in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 1846(p.K1846SfsTer11) was detected. This frameshift variant is not reported in both the 1000 genomes and gnomAD databases. This variant is predicted to be damaging by Mutation taster and the region is conserved across species. There are 14 downstream pathogenic loss of function variants, with the furthest variant being 80 residues downstream of this variant. This indicates that the region is critical to protein function. This gene has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The observed variant is a loss of function variant in this gene, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 448 others. The observed variant has been previously classified as Pathogenic in ClinVar (Variation ID 189881 as of 2021-03-04) with respect to severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -
Developmental and epileptic encephalopathy 6B Pathogenic:2
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PVS1,PS2,PM2 -
SCN1A Seizure Disorders Pathogenic:1
The SCN1A c.5536_5539del (p.Lys1846SerfsTer11) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in individuals with a phenotype consistent with SCN1A seizure disorders, the majority of which were found in a de novo state (PMID: 11359211; 18413471; 20431604; 21719429; 34055682; 34145886; 35701389; 35886038). The p.Lys1846SerfsTer11 variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The variant was identified in a de novo state. Based on the available evidence, the c.5536_5539del (p.Lys1846SerfsTer11) variant is classified as pathogenic for SCN1A seizure disorders. -
Inborn genetic diseases Pathogenic:1
The c.5536_5539delAAAC pathogenic mutation, located in coding exon 26 of the SCN1A gene, results from a deletion of 4 nucleotides at nucleotide positions 5536 to 5539, causing a translational frameshift with a predicted alternate stop codon (p.K1846Sfs*11). This mutation has been detected in several individuals with Dravet syndrome, severe myoclonic epilepsy of infancy, and/or epileptic encephalopathy (Claes L et al. Am. J. Hum. Genet., 2001 Jun;68:1327-32; Heron SE et al. J. Med. Genet., 2010 Feb;47:137-41; Claes LR et al. Hum. Mutat., 2009 Oct;30:E904-20); Sun H et al. J. Hum. Genet., 2010 Jul;55:421-7; Spatola M et al. Eur. Neurol., 2013 Nov;69:119-21; Catarino CB et al. Brain, 2011 Oct;134:2982-3010; Wallace RH et al. Neurology, 2003 Sep;61:765-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This sequence change creates a premature translational stop signal (p.Lys1846Serfs*11) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acid(s) of the SCN1A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (also known as severe myoclonic epilepsy of infancy) (PMID: 11359211, 14504318, 21719429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189881). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at