rs143734912
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BS1_SupportingBS2
The NM_001040142.2(SCN2A):c.1841C>T(p.Pro614Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000793 in 1,614,144 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P614P) has been classified as Likely benign.
Frequency
Consequence
NM_001040142.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.1841C>T | p.Pro614Leu | missense_variant | 12/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.1841C>T | p.Pro614Leu | missense_variant | 12/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.1841C>T | p.Pro614Leu | missense_variant | 12/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.1841C>T | p.Pro614Leu | missense_variant | 12/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251204Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135782
GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000729 AC XY: 53AN XY: 727244
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74442
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 13, 2017 | - - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 614 of the SCN2A protein (p.Pro614Leu). This variant is present in population databases (rs143734912, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 33004838). ClinVar contains an entry for this variant (Variation ID: 207091). 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 SCN2A protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2021 | Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the cytoplasmic loop between the first and second homologous domains; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at