NM_001165963.4:c.2354T>C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP2PP3_ModeratePP5_Moderate
The NM_001165963.4(SCN1A):c.2354T>C(p.Met785Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.2354T>C | p.Met785Thr | missense_variant | Exon 16 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.2354T>C | p.Met785Thr | missense_variant | Exon 15 of 28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.2321T>C | p.Met774Thr | missense_variant | Exon 13 of 26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.2270T>C | p.Met757Thr | missense_variant | Exon 13 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (Lek et al., 2016); This substitution is predicted to be within the transmembrane segment S1 of the second homologous domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29655203, 21248271, 31864146, 32090326) -
Developmental and epileptic encephalopathy 6B Pathogenic:1
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SCN1A related disorder (ClinVar ID: VCV000206938). Different missense changes at the same codon (p.Met785Arg, p.Met785Ile, p.Met785Leu, p.Met785Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189917, VCV000521545, VCV000581674, VCV001066611 /PMID: 26096185). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at