2-166280396-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001365536.1(SCN9A):c.2304G>A(p.Met768Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000085 in 1,587,750 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M768K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001365536.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.2304G>A | p.Met768Ile | missense_variant | 14/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.1029+3149C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.2304G>A | p.Met768Ile | missense_variant | 14/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1707+3149C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000377 AC: 8AN: 212256Hom.: 0 AF XY: 0.0000352 AC XY: 4AN XY: 113678
GnomAD4 exome AF: 0.0000899 AC: 129AN: 1435590Hom.: 0 Cov.: 30 AF XY: 0.0000984 AC XY: 70AN XY: 711314
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74336
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2019 | The p.M757I variant (also known as c.2271G>A), located in coding exon 13 of the SCN9A gene, results from a G to A substitution at nucleotide position 2271. The methionine at codon 757 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 757 of the SCN9A protein (p.Met757Ile). This variant is present in population databases (rs201736678, gnomAD 0.007%). This missense change has been observed in individual(s) with small fiber neuropathy (PMID: 30554136). ClinVar contains an entry for this variant (Variation ID: 254096). 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 SCN9A 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 30, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at