rs1553463516
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001040142.2(SCN2A):c.5125del(p.Gln1709LysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SCN2A
NM_001040142.2 frameshift
NM_001040142.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.725
Genes affected
SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-165388929-TC-T is Pathogenic according to our data. Variant chr2-165388929-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 464914.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.5125del | p.Gln1709LysfsTer12 | frameshift_variant | 27/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.5125del | p.Gln1709LysfsTer12 | frameshift_variant | 27/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.5125del | p.Gln1709LysfsTer12 | frameshift_variant | 27/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.5125del | p.Gln1709LysfsTer12 | frameshift_variant | 27/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln1709Lysfs*12) in the SCN2A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 297 amino acid(s) of the SCN2A protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 464914). This variant disrupts a region of the SCN2A protein in which other variant(s) (p.Ala1773Thr) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at