rs794726778
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001353961.2(SCN1A):c.-592C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SCN1A
NM_001353961.2 5_prime_UTR_premature_start_codon_gain
NM_001353961.2 5_prime_UTR_premature_start_codon_gain
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.58
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.625
PP5
Variant 2-166043878-G-A is Pathogenic according to our data. Variant chr2-166043878-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.1834C>T | p.Arg612* | stop_gained | Exon 14 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.1834C>T | p.Arg612* | stop_gained | Exon 13 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.1834C>T | p.Arg612* | stop_gained | Exon 11 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.1 | c.1834C>T | p.Arg612* | stop_gained | Exon 11 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727240
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727240
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe myoclonic epilepsy in infancy Pathogenic:3
| Pathogenic, criteria provided, single submitter | research | Center for Bioinformatics, Peking University | Dec 20, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | The stop gained NM_001165963.4(SCN1A):c.1834C>T (p.Arg612Ter) has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 189941 as of 2021-07-01). The p.Arg612Ter variant is novel (not in any individuals) in gnomAD. The p.Arg612Ter variant is novel (not in any individuals) in 1kG. This variant is predicted to cause loss of normal protein function through protein truncation. This variant is a stop gained variant which occurs in an exon of SCN1A upstream of where nonsense mediated decay is predicted to occur. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 369 downstream pathogenic loss of function variants, with the furthest variant being 1314 residues downstream of this variant. This indicates that the region is critical to protein function. The gene SCN1A 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 p.Arg612Ter variant is a loss of function variant in the gene SCN1A, 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 503 others. This variant has been reported to be de novo in individuals affected with severe myoclonic epilepsy of infancy by Sun H et al., 2008. Loss-of-function variants in SCN1A are known to be pathogenic by Harkin L A et al., 2007. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 25, 2021 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg612*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with severe myoclonic epilepsy of infancy (PMID: 18554359). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189941). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.96, 0.97, 0.98, 0.97
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at