rs548056312
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001040142.2(SCN2A):c.1939G>A(p.Ala647Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,046 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A647A) has been classified as Likely benign.
Frequency
Consequence
NM_001040142.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.1939G>A | p.Ala647Thr | missense_variant | 12/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.1939G>A | p.Ala647Thr | missense_variant | 12/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.1939G>A | p.Ala647Thr | missense_variant | 12/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.1939G>A | p.Ala647Thr | missense_variant | 12/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250078Hom.: 1 AF XY: 0.0000444 AC XY: 6AN XY: 135220
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461756Hom.: 2 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727152
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74456
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2014 | p.Ala647Thr (GCT>ACT): c.1939 G>A in exon 12 of the SCN2A gene (NM_021007.2). A variant of unknown significance has been identified in the SCN2A gene. The A647T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A647T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The variant alters a position in the cytoplasmic loop between the 1st and 2nd homologous domains of the SCN2A protein (Shi et al., 2012). A missense mutation in a nearby residue (D649N) has been reported in association with Dravet syndrome, supporting the functional importance of this region of the protein. The A647T substitution occurs at a position that is conserved in mammals; however, Threonine is observed at this position in more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the this variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether the A647T variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s). - |
Seizures, benign familial infantile, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at