3-38728733-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006514.4(SCN10A):ā€‹c.2449C>Gā€‹(p.Arg817Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817Q) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

SCN10A
NM_006514.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.135
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11205119).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN10ANM_006514.4 linkuse as main transcriptc.2449C>G p.Arg817Gly missense_variant 16/28 ENST00000449082.3 NP_006505.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN10AENST00000449082.3 linkuse as main transcriptc.2449C>G p.Arg817Gly missense_variant 16/281 NM_006514.4 ENSP00000390600 P4
SCN10AENST00000655275.1 linkuse as main transcriptc.2476C>G p.Arg826Gly missense_variant 16/28 ENSP00000499510
SCN10AENST00000643924.1 linkuse as main transcriptc.2449C>G p.Arg817Gly missense_variant 15/27 ENSP00000495595 A1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152104
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 16, 2023The p.R817G variant (also known as c.2449C>G), located in coding exon 15 of the SCN10A gene, results from a C to G substitution at nucleotide position 2449. The arginine at codon 817 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
3.2
DANN
Benign
0.85
DEOGEN2
Uncertain
0.56
D;.;D;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.060
N
LIST_S2
Benign
0.57
.;T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
0.87
L;.;L;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.7
N;.;.;.
REVEL
Uncertain
0.30
Sift
Benign
0.10
T;.;.;.
Sift4G
Benign
0.25
T;.;.;.
Polyphen
0.0020
B;.;B;.
Vest4
0.26
MutPred
0.45
Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);
MVP
0.41
MPC
0.079
ClinPred
0.031
T
GERP RS
-1.1
Varity_R
0.057
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763084100; hg19: chr3-38770224; API