rs796053072
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001165963.4(SCN1A):c.3724_3725dupAT(p.Asp1243LeufsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I1242I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001165963.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.3724_3725dupAT | p.Asp1243LeufsTer28 | frameshift_variant | Exon 22 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.3724_3725dupAT | p.Asp1243LeufsTer28 | frameshift_variant | Exon 21 of 28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.3691_3692dupAT | p.Asp1232LeufsTer28 | frameshift_variant | Exon 19 of 26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.3640_3641dupAT | p.Asp1215LeufsTer28 | frameshift_variant | Exon 19 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1457306Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725026
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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c.3724_3725dupAT: p.Asp1243LeufsX28 (D1243LfsX28) in exon 19 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are duplicated in bases is TATAT{dupAT}TGAT. The c.3724_3725dupAT pathogenic variant in the SCN1A gene has been reported previously, using alternate nomenclature, as a de novo mutation in an individual with myoclonic epilepsy in infancy (Marini et al., 2007) and in another individual with intractable epilepsy in which the inheritance pattern was unknown (Wang et al., 2012). The c.3724_3725dupAT pathogenic variant causes a frameshift starting with codon Aspartic acid 1243, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Asp1243LeufsX28. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The presence of c.3724_3725dupAT is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in EPILEPSY panel(s). -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp1243Leufs*28) 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 epilepsy (PMID: 17561957, 23195492). This variant is also known as p.I1242ins1270X. ClinVar contains an entry for this variant (Variation ID: 206910). For these reasons, this variant has been classified as Pathogenic. -
Developmental and epileptic encephalopathy 6B Pathogenic:1
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000206910 /PMID: 17561957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at