2-166277134-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001365536.1(SCN9A):c.2723G>A(p.Trp908Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,020 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001365536.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.2723G>A | p.Trp908Ter | stop_gained | 16/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.916C>T | non_coding_transcript_exon_variant | 8/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.2723G>A | p.Trp908Ter | stop_gained | 16/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1594C>T | non_coding_transcript_exon_variant | 15/19 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74242
ClinVar
Submissions by phenotype
Channelopathy-associated congenital insensitivity to pain, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Mendelics | Nov 26, 2013 | - - |
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 | Oct 25, 2021 | This sequence change creates a premature translational stop signal (p.Trp897*) in the SCN9A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN9A are known to be pathogenic (PMID: 17470132, 19304393). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individuals with congenital insensitivity to pain (PMID: 17167479, 30795902). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Y897*. ClinVar contains an entry for this variant (Variation ID: 202190). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Generalized epilepsy with febrile seizures plus, type 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.2690G>A;p.(Trp897*) variant creates a premature translational stop signal in the SCN9A gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 202190; PMID: 25309764) - PS4_moderate. This variant is not present in population databases (rs794729216, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at