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GeneBe

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. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN10A
NM_006514.4 missense

Scores

1
6
11

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/exons MANE UniProt
SCN10ANM_006514.4 linkuse as main transcriptc.5863G>A p.Gly1955Arg missense_variant 28/28 ENST00000449082.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN10AENST00000449082.3 linkuse as main transcriptc.5863G>A p.Gly1955Arg missense_variant 28/281 NM_006514.4 P4
SCN10AENST00000655275.1 linkuse as main transcriptc.5887G>A p.Gly1963Arg missense_variant 28/28
SCN10AENST00000643924.1 linkuse as main transcriptc.5860G>A p.Gly1954Arg missense_variant 27/27 A1

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
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 15, 2022In 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2024The 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
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;.
MutationTaster
Benign
1.0
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