3-38697357-C-T

Variant summary

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

The NM_006514.4(SCN10A):​c.5863G>A​(p.Gly1955Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN10A
NM_006514.4 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.19
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]

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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=0.13308486).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN10ANM_006514.4 linkc.5863G>A p.Gly1955Arg missense_variant Exon 28 of 28 ENST00000449082.3 NP_006505.4 Q9Y5Y9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN10AENST00000449082.3 linkc.5863G>A p.Gly1955Arg missense_variant Exon 28 of 28 1 NM_006514.4 ENSP00000390600.2 Q9Y5Y9
SCN10AENST00000643924.1 linkc.5860G>A p.Gly1954Arg missense_variant Exon 27 of 27 ENSP00000495595.1 A0A2R8Y6J6
SCN10AENST00000655275.1 linkc.5887G>A p.Gly1963Arg missense_variant Exon 28 of 28 ENSP00000499510.1 A0A590UJM0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brugada syndrome Uncertain:1
Jun 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 809452). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1955 of the SCN10A protein (p.Gly1955Arg). -

Cardiovascular phenotype Uncertain:1
Feb 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G1955R variant (also known as c.5863G>A), located in coding exon 27 of the SCN10A gene, results from a G to A substitution at nucleotide position 5863. The glycine at codon 1955 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
T;.;T;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.036
N
LIST_S2
Benign
0.34
.;T;T;T
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
0.0
N;.;N;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.0
N;.;.;.
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Uncertain
0.057
T;.;.;.
Polyphen
0.010
B;.;B;.
Vest4
0.29
MutPred
0.24
Loss of glycosylation at P1956 (P = 0.0307);Loss of glycosylation at P1956 (P = 0.0307);Loss of glycosylation at P1956 (P = 0.0307);.;
MVP
0.62
MPC
0.21
ClinPred
0.53
D
GERP RS
4.0
Varity_R
0.19
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1575913891; hg19: chr3-38738848; API