chr3-38722348-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_006514.4(SCN10A):āc.3417G>Cā(p.Trp1139Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,613,972 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
SCN10A
NM_006514.4 missense
NM_006514.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 6.08
Genes affected
SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.3417G>C | p.Trp1139Cys | missense_variant | 20/28 | ENST00000449082.3 | NP_006505.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.3417G>C | p.Trp1139Cys | missense_variant | 20/28 | 1 | NM_006514.4 | ENSP00000390600.2 | ||
SCN10A | ENST00000643924.1 | c.3414G>C | p.Trp1138Cys | missense_variant | 19/27 | ENSP00000495595.1 | ||||
SCN10A | ENST00000655275.1 | c.3441G>C | p.Trp1147Cys | missense_variant | 20/28 | ENSP00000499510.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152094Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000954 AC: 24AN: 251452Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135898
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GnomAD4 exome AF: 0.000107 AC: 157AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76AN XY: 727240
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74280
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2023 | Reported in association with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy (Behr et al., 2015; Te Riele et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26733327, 25691538) - |
Episodic pain syndrome, familial, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 03, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1139 of the SCN10A protein (p.Trp1139Cys). This variant is present in population databases (rs143744796, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome or arrhythmogenic right ventricular cardiomyopathy (PMID: 25691538, 26733327). ClinVar contains an entry for this variant (Variation ID: 532064). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2020 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.
Sift4G
Uncertain
D;.;.;.
Polyphen
D;.;D;.
Vest4
MutPred
Gain of glycosylation at T1144 (P = 0.0221);Gain of glycosylation at T1144 (P = 0.0221);Gain of glycosylation at T1144 (P = 0.0221);.;
MVP
MPC
ClinPred
D
GERP RS
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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