NM_001165963.4:c.4284+2T>C
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001165963.4(SCN1A):c.4284+2T>C variant causes a splice donor, intron 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001165963.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4284+2T>C | splice_donor_variant, intron_variant | Intron 24 of 28 | NM_001165963.4 | ENSP00000501589.1 | ||||
SCN1A | ENST00000303395.9 | c.4284+2T>C | splice_donor_variant, intron_variant | Intron 23 of 27 | 5 | ENSP00000303540.4 | ||||
SCN1A | ENST00000375405.7 | c.4251+2T>C | splice_donor_variant, intron_variant | Intron 21 of 25 | 5 | ENSP00000364554.3 | ||||
SCN1A | ENST00000409050.2 | c.4200+2T>C | splice_donor_variant, intron_variant | Intron 23 of 27 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The c.4284+2 T>C splice site variant in the SCN1A gene has been previously reported in association with Dravet syndrome (Wang et al., 2012; Xiong et al., 2016). This pathogenic variant destroys the canonical splice donor site in intron 21, and is expected to cause abnormal gene splicing. This variant is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the third homologous domain. Additionally, the c.4284+2 T>C variant is not observed in large population cohorts (Lek et al., 2016). Furthermore, nearby splice site variants in this intron have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorders (Stenson et al., 2014). Therefore, the presence of this variant is consistent with the diagnosis of an SCN1A-related disorder in this individual. -
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Seizure Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at