rs147623238
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001365536.1(SCN9A):āc.3051G>Cā(p.Lys1017Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,596,900 control chromosomes in the GnomAD database, including 1 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 0.0014 ( 1 hom., cov: 31)
Exomes š: 0.00015 ( 0 hom. )
Consequence
SCN9A
NM_001365536.1 missense
NM_001365536.1 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 0.0990
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-166272699-C-G is Benign according to our data. Variant chr2-166272699-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246380.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.3051G>C | p.Lys1017Asn | missense_variant | 17/27 | ENST00000642356.2 | NP_001352465.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.3051G>C | p.Lys1017Asn | missense_variant | 17/27 | NM_001365536.1 | ENSP00000495601.1 | |||
SCN9A | ENST00000303354.11 | c.3051G>C | p.Lys1017Asn | missense_variant | 17/27 | 5 | ENSP00000304748.7 | |||
SCN9A | ENST00000409672.5 | c.3018G>C | p.Lys1006Asn | missense_variant | 17/27 | 5 | ENSP00000386306.1 | |||
SCN9A | ENST00000645907.1 | c.3018G>C | p.Lys1006Asn | missense_variant | 17/27 | ENSP00000495983.1 |
Frequencies
GnomAD3 genomes AF: 0.00137 AC: 208AN: 151620Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000383 AC: 91AN: 237294Hom.: 0 AF XY: 0.000288 AC XY: 37AN XY: 128628
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GnomAD4 exome AF: 0.000153 AC: 221AN: 1445164Hom.: 0 Cov.: 31 AF XY: 0.000133 AC XY: 95AN XY: 716928
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GnomAD4 genome AF: 0.00143 AC: 217AN: 151736Hom.: 1 Cov.: 31 AF XY: 0.00138 AC XY: 102AN XY: 74110
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2024 | Reported as a variant of uncertain significance in a patient with epilepsy (PMID: 36539902); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 36539902) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 28, 2017 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2021 | 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. - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
SCN9A-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 12, 2019 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;.;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;M;.;.;M;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;.;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;.;D
Sift4G
Uncertain
D;T;.;.;.;T
Vest4
MutPred
Loss of methylation at K1006 (P = 0.0265);.;Loss of methylation at K1006 (P = 0.0265);Loss of methylation at K1006 (P = 0.0265);.;.;
MVP
MPC
ClinPred
T
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Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at