rs192493052
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_006514.4(SCN10A):c.3556C>A(p.Leu1186Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
SCN10A
NM_006514.4 missense
NM_006514.4 missense
Scores
4
12
2
Clinical Significance
Conservation
PhyloP100: 1.46
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.3556C>A | p.Leu1186Met | missense_variant | 21/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.3556C>A | p.Leu1186Met | missense_variant | 21/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.3580C>A | p.Leu1194Met | missense_variant | 21/28 | ||||
SCN10A | ENST00000643924.1 | c.3553C>A | p.Leu1185Met | missense_variant | 20/27 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251428Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135882
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727236
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1186 of the SCN10A protein (p.Leu1186Met). This variant is present in population databases (rs192493052, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 220957). 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 expected to disrupt SCN10A protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2021 | The p.L1186M variant (also known as c.3556C>A), located in coding exon 20 of the SCN10A gene, results from a C to A substitution at nucleotide position 3556. The leucine at codon 1186 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in a sudden cardiac arrest cohort; however, details were limited (Giudicessi JR et al. Int J Cardiol, 2018 Nov;270:214-220). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.
Sift4G
Pathogenic
D;.;.;.
Polyphen
D;.;D;.
Vest4
MVP
MPC
ClinPred
D
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