2-165992194-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_001165963.4(SCN1A):c.5081A>G(p.Tyr1694Cys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1694D) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.5081A>G | p.Tyr1694Cys | missense_variant | 29/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-23419T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.5081A>G | p.Tyr1694Cys | missense_variant | 29/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-23419T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 68650). This variant is also known as Tyr1684Cys. This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and generalized epilepsy with febrile seizures (PMID: 14738421, 19586930, 28202706). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1694 of the SCN1A protein (p.Tyr1694Cys). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 29, 2016 | - - |
Severe myoclonic epilepsy in infancy Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at