2-166046888-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001165963.4(SCN1A):c.1259C>A(p.Ala420Asp) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A420V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1259C>A | p.Ala420Asp | missense_variant | 12/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.1259C>A | p.Ala420Asp | missense_variant | 12/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+10758G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy 6B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Aug 24, 2021 | The variant c.1259C>A (p.Ala420Asp) in the SCN1A gene is reported as uncertain in ClinVar (Variation ID:283002). The variant has been reported as likely pathogenic by Butler et al. (2017) in a patient with epilepsy whose detailed phenotype was not available. Furthermore, the variant falls into a region rich in missense mutations reported as pathogenic or likely pathogenic (Clinvar), one of which affects the same nucelotide, causing a different amino acid change (c.1259C>T, p.Ala420Val, Clinvar variation ID:189996). There is no information on frequency in gnomAD database. The nucleotide position is conserved across 35 mammalian species(GERP RS: 5.31). In silico analysis indicates that the variant might be damaging. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 28, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at