chr2-166288566-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_001365536.1(SCN9A):c.1185C>G(p.Asn395Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N395I) 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_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.1185C>G | p.Asn395Lys | missense_variant | 10/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.1030-5999G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.1185C>G | p.Asn395Lys | missense_variant | 10/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1708-5999G>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2015 | The N395K missense variant in the SCN9A gene has been reported previously in association with erythermalgia (Zhang et al., 2007). Functional studies show that the N395 residue, which is located in the local anesthetic binding site, is critical for lidocaine binding, and N395K was associated with altered channel function and altered lidocaine binding (Sheets et al., 2007). The N395K variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a semi-conservative amino acid substitution, which occurs at a position in the protein that is conserved across species. Additionally, a different nucleotide substitution (c.1185 C>A) resulting in the same amino acid substitution (N395K) has also been published in association with primary erythermalgia (Drenth et al., 2005). Therefore, the presence of the N395K variant is consistent with a diagnosis of an SCN9A-related disorder - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at