rs200823610
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001365536.1(SCN9A):c.1348A>G(p.Ile450Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,582,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I450T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001365536.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 27 | ENST00000642356.2 | NP_001352465.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 27 | NM_001365536.1 | ENSP00000495601.1 | |||
SCN9A | ENST00000303354.11 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 27 | 5 | ENSP00000304748.7 | |||
SCN9A | ENST00000409672.5 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 27 | 5 | ENSP00000386306.1 | |||
SCN9A | ENST00000645907.1 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 27 | ENSP00000495983.1 | ||||
SCN9A | ENST00000454569.6 | c.1348A>G | p.Ile450Val | missense_variant | Exon 11 of 15 | 1 | ENSP00000413212.2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000519 AC: 11AN: 211932Hom.: 0 AF XY: 0.0000436 AC XY: 5AN XY: 114746
GnomAD4 exome AF: 0.0000629 AC: 90AN: 1430150Hom.: 0 Cov.: 31 AF XY: 0.0000663 AC XY: 47AN XY: 709386
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74474
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: SCN9A c.1348A>G (p.Ile450Val) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 211932 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SCN9A causing Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive (5.2e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1348A>G in individuals affected with SCN9A-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 538437). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The p.I450V variant (also known as c.1348A>G), located in coding exon 10 of the SCN9A gene, results from an A to G substitution at nucleotide position 1348. The isoleucine at codon 450 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 450 of the SCN9A protein (p.Ile450Val). This variant is present in population databases (rs200823610, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 538437). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. 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