rs764965507
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_006514.4(SCN10A):c.1788G>T(p.Leu596Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
SCN10A
NM_006514.4 missense
NM_006514.4 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 0.235
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.27060816).
BS2
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.1788G>T | p.Leu596Phe | missense_variant | 13/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.1788G>T | p.Leu596Phe | missense_variant | 13/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.1815G>T | p.Leu605Phe | missense_variant | 13/28 | ||||
SCN10A | ENST00000643924.1 | c.1788G>T | p.Leu596Phe | missense_variant | 12/27 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152226Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
4
AN:
152226
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250780Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135520
GnomAD3 exomes
AF:
AC:
3
AN:
250780
Hom.:
AF XY:
AC XY:
2
AN XY:
135520
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460744Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3AN XY: 726700
GnomAD4 exome
AF:
AC:
8
AN:
1460744
Hom.:
Cov.:
29
AF XY:
AC XY:
3
AN XY:
726700
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74372
GnomAD4 genome
AF:
AC:
4
AN:
152226
Hom.:
Cov.:
33
AF XY:
AC XY:
4
AN XY:
74372
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2024 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 28, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 596 of the SCN10A protein (p.Leu596Phe). This variant is present in population databases (rs764965507, gnomAD 0.009%). 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: 451515). 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 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2022 | The p.L596F variant (also known as c.1788G>T), located in coding exon 12 of the SCN10A gene, results from a G to T substitution at nucleotide position 1788. The leucine at codon 596 is replaced by phenylalanine, an amino acid with highly 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;.;.;.
REVEL
Uncertain
Sift
Benign
D;.;.;.
Sift4G
Benign
T;.;.;.
Polyphen
D;.;D;.
Vest4
MutPred
Gain of glycosylation at Y600 (P = 0.0031);Gain of glycosylation at Y600 (P = 0.0031);Gain of glycosylation at Y600 (P = 0.0031);Gain of glycosylation at Y600 (P = 0.0031);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at