rs121908910
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001365536.1(SCN9A):c.3019C>T(p.Arg1007Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,584,382 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1007H) has been classified as Likely benign.
Frequency
Consequence
NM_001365536.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.3019C>T | p.Arg1007Cys | missense_variant | 17/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.870-4357G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.3019C>T | p.Arg1007Cys | missense_variant | 17/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1548-4357G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151586Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000176 AC: 4AN: 226882Hom.: 0 AF XY: 0.0000245 AC XY: 3AN XY: 122620
GnomAD4 exome AF: 0.0000195 AC: 28AN: 1432680Hom.: 0 Cov.: 31 AF XY: 0.0000225 AC XY: 16AN XY: 709628
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151702Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74092
ClinVar
Submissions by phenotype
Paroxysmal extreme pain disorder Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2006 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 12, 2021 | - - |
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 6356). This missense change has been observed in individuals with autosomal dominant paroxysmal extreme pain disorder (PMID: 17145499). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908910, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 996 of the SCN9A protein (p.Arg996Cys). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2023 | Identified in an individual with epilepsy in published literature; however, no further clinical or segregation information was provided (Truty et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 17145499, 31440721) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at