rs794726778
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
Consequence
NM_001353961.2 5_prime_UTR_premature_start_codon_gain
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.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 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Severe myoclonic epilepsy in infancy Pathogenic:3
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. -
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Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at