rs182650126
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001365536.1(SCN9A):āc.2248A>Gā(p.Ile750Val) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,589,074 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0027 ( 1 hom., cov: 32)
Exomes š: 0.0035 ( 10 hom. )
Consequence
SCN9A
NM_001365536.1 missense
NM_001365536.1 missense
Scores
1
10
6
Clinical Significance
Conservation
PhyloP100: 4.15
Genes affected
SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.012462795).
BP6
?
Variant 2-166280452-T-C is Benign according to our data. Variant chr2-166280452-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157597.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Benign=2, Uncertain_significance=1}. Variant chr2-166280452-T-C is described in Lovd as [Likely_benign]. Variant chr2-166280452-T-C is described in Lovd as [Pathogenic].
BS2
?
High Homozygotes in GnomAdExome4 at 10 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.2248A>G | p.Ile750Val | missense_variant | 14/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.1029+3205T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.2248A>G | p.Ile750Val | missense_variant | 14/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1707+3205T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00268 AC: 408AN: 152086Hom.: 1 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00245 AC: 515AN: 210268Hom.: 2 AF XY: 0.00234 AC XY: 264AN XY: 112770
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GnomAD4 exome AF: 0.00354 AC: 5089AN: 1436870Hom.: 10 Cov.: 30 AF XY: 0.00346 AC XY: 2463AN XY: 712154
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GnomAD4 genome ? AF: 0.00267 AC: 407AN: 152204Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194AN XY: 74408
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:14
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2021 | This variant is associated with the following publications: (PMID: 19763161, 24820863, 24737233, 32707200, 22539570, 27301361, 28073787, 28235406, 23891399, 29176367, 27608006, 27916648, 28488083, 30478917, 31664448, 22826602, 21698661) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 28, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | SCN9A: BS2 - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 05, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Aug 19, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2017 | - - |
Small fiber neuropathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
Primary erythromelalgia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Inherited Erythromelalgia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 03, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
SCN9A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 27, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Paroxysmal extreme pain disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;N;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;D;.
Sift4G
Uncertain
D;D;.;.;.;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at