rs757989638
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001365536.1(SCN9A):c.3125C>T(p.Thr1042Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
SCN9A
NM_001365536.1 missense
NM_001365536.1 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 5.20
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SCN9A | NM_001365536.1 | c.3125C>T | p.Thr1042Ile | missense_variant | 17/27 | ENST00000642356.2 | |
| SCN1A-AS1 | NR_110260.1 | n.870-4463G>A | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN9A | ENST00000642356.2 | c.3125C>T | p.Thr1042Ile | missense_variant | 17/27 | NM_001365536.1 | P1 | ||
| SCN1A-AS1 | ENST00000651574.1 | n.1548-4463G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.0000527 AC: 8AN: 151804Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000242 AC: 6AN: 248386Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134734
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461236Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726890
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GnomAD4 genome 0.0000527 AC: 8AN: 151922Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 5AN XY: 74212
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary erythromelalgia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | The p.T1031I variant (also known as c.3092C>T), located in coding exon 16 of the SCN9A gene, results from a C to T substitution at nucleotide position 3092. The threonine at codon 1031 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 471106). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1031 of the SCN9A protein (p.Thr1031Ile). This variant is present in population databases (rs757989638, gnomAD 0.009%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 27956748). - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | The SCN9A c.3092C>T; p.Thr1031Ile variant (rs757989638) is reported in the literature in an individual affected with autism (Rubinstein 2018), though to our knowledge it has not been reported in individuals with neuropathy. This variant is found on seven chromosomes (7/279778 alleles) in the Genome Aggregation Database. The threonine at codon 1031 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.514). However, given the lack of clinical and functional data, the significance of the p.Thr1031Ile variant is uncertain at this time. References: Rubinstein M et al. Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Mol Psychiatry. 2018 Feb;23(2):231-239. PMID: 27956748. - |
Paroxysmal extreme pain disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;.;D;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;.;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;D
Sift4G
Benign
T;T;.;.;.;T
Vest4
MutPred
Loss of disorder (P = 0.0696);.;Loss of disorder (P = 0.0696);Loss of disorder (P = 0.0696);.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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