rs373780066
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001040142.2(SCN2A):āc.3383T>Cā(p.Met1128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1128V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040142.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.3383T>C | p.Met1128Thr | missense_variant | 17/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.3383T>C | p.Met1128Thr | missense_variant | 17/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.3383T>C | p.Met1128Thr | missense_variant | 17/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.3383T>C | p.Met1128Thr | missense_variant | 17/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461434Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727024
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2017 | The p.M1128T variant (also known as c.3383T>C), located in coding exon 16 of the SCN2A gene, results from a T to C substitution at nucleotide position 3383. The methionine at codon 1128 is replaced by threonine, an amino acid with similar properties. This alteration was detected in an individual with refractory, repetitive (100 per day) generalized convulsive seizures which onset at age 6. As seizures persisted, his intellect regressed and he is now severely intellectually delayed as an adult (Kobayashi K et al. Epilepsy Res., 2012 Nov;102:109-12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1128 of the SCN2A protein (p.Met1128Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 22591750, 32090326). ClinVar contains an entry for this variant (Variation ID: 589603). 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 not expected to disrupt SCN2A protein function with a negative 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at