rs141648641
Positions:
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_006514.4(SCN10A):c.5605C>T(p.Arg1869Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,614,112 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00058 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 7 hom. )
Consequence
SCN10A
NM_006514.4 missense
NM_006514.4 missense
Scores
9
4
6
Clinical Significance
Conservation
PhyloP100: 7.22
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 Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.013748288).
BP6
Variant 3-38697615-G-A is Benign according to our data. Variant chr3-38697615-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 420024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38697615-G-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 89 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.5605C>T | p.Arg1869Cys | missense_variant | 28/28 | ENST00000449082.3 | NP_006505.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.5605C>T | p.Arg1869Cys | missense_variant | 28/28 | 1 | NM_006514.4 | ENSP00000390600 | P4 | |
SCN10A | ENST00000655275.1 | c.5629C>T | p.Arg1877Cys | missense_variant | 28/28 | ENSP00000499510 | ||||
SCN10A | ENST00000643924.1 | c.5602C>T | p.Arg1868Cys | missense_variant | 27/27 | ENSP00000495595 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000585 AC: 89AN: 152158Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000999 AC: 251AN: 251126Hom.: 2 AF XY: 0.000899 AC XY: 122AN XY: 135700
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GnomAD4 exome AF: 0.000527 AC: 770AN: 1461836Hom.: 7 Cov.: 32 AF XY: 0.000557 AC XY: 405AN XY: 727226
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GnomAD4 genome AF: 0.000584 AC: 89AN: 152276Hom.: 2 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | SCN10A: BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2019 | This variant is associated with the following publications: (PMID: 27711072, 26733327, 24998131, 29016797, 30821013, 32948286) - |
Brugada syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 16, 2023 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2019 | This alteration is classified as 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.
Sift4G
Pathogenic
D;.;.;.
Polyphen
D;.;D;.
Vest4
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