NM_001165963.4:c.5797delC
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
This summary comes from the ClinGen Evidence Repository: The c.5797del variant in SCN1A is a single nucleotide deletion predicted to cause a frameshift at amino acid position 1933 leading to a premature stop codon (p.Arg1933Glufs*3). The variant is located within the last exon and thus predicted to escape nonsense mediated decay. The truncated region is not known to be important for protein function, as missense variants reported in the region do not meet PLP per these criteria. Furthermore, LOF variants within this exon are relatively common in gnomAD v4.1. As such, this variant does not meet criteria to apply PVS1. This variant has been identified in a family in which 2 affected siblings with developmental and epileptic encephalopathy (DEE) harbored the variant, in addition to an unaffected parent and 2 unaffected siblings (LabCorp Genetics, Inc. internal data). Given the severity of the phenotype and presence in multiple unaffected family members, this case was not included as evidence for PS4. The variant is absent from the population database, gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting. (version 1.0, approved September 24, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA269784/MONDO:0018214/067
Frequency
Consequence
NM_001165963.4 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN1A | NM_001165963.4 | MANE Select | c.5797delC | p.Arg1933GlufsTer3 | frameshift | Exon 29 of 29 | NP_001159435.1 | ||
| SCN1A | NM_001202435.3 | c.5797delC | p.Arg1933GlufsTer3 | frameshift | Exon 28 of 28 | NP_001189364.1 | |||
| SCN1A | NM_001353948.2 | c.5797delC | p.Arg1933GlufsTer3 | frameshift | Exon 27 of 27 | NP_001340877.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | MANE Select | c.5797delC | p.Arg1933GlufsTer3 | frameshift | Exon 29 of 29 | ENSP00000501589.1 | ||
| SCN1A | ENST00000303395.9 | TSL:5 | c.5797delC | p.Arg1933GlufsTer3 | frameshift | Exon 28 of 28 | ENSP00000303540.4 | ||
| SCN1A | ENST00000375405.7 | TSL:5 | c.5764delC | p.Arg1922GlufsTer3 | frameshift | Exon 26 of 26 | ENSP00000364554.3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1933Glufs*3) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the SCN1A protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 130208). This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Arg1988Trp) have been determined to be pathogenic (PMID: 23708187; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1
not provided Pathogenic:1
Frameshift variant predicted to result in abnormal protein length as the last 77 amino acid(s) are replaced with 2 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32347949)
Generalized epilepsy with febrile seizures plus Uncertain:1
The c.5797del variant in SCN1A is a single nucleotide deletion predicted to cause a frameshift at amino acid position 1933 leading to a premature stop codon (p.Arg1933Glufs*3). The variant is located within the last exon and thus predicted to escape nonsense mediated decay. The truncated region is not known to be important for protein function, as missense variants reported in the region do not meet PLP per these criteria. Furthermore, LOF variants within this exon are relatively common in gnomAD v4.1. As such, this variant does not meet criteria to apply PVS1. This variant has been identified in a family in which 2 affected siblings with developmental and epileptic encephalopathy (DEE) harbored the variant, in addition to an unaffected parent and 2 unaffected siblings (LabCorp Genetics, Inc. internal data). Given the severity of the phenotype and presence in multiple unaffected family members, this case was not included as evidence for PS4. The variant is absent from the population database, gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting. (version 1.0, approved September 24, 2024).
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at