chr3-38726851-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006514.4(SCN10A):​c.2842G>A​(p.Val948Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V948L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

1
18

Clinical Significance

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

Conservation

PhyloP100: 0.346
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1783796).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN10ANM_006514.4 linkc.2842G>A p.Val948Met missense_variant 17/28 ENST00000449082.3 NP_006505.4 Q9Y5Y9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN10AENST00000449082.3 linkc.2842G>A p.Val948Met missense_variant 17/281 NM_006514.4 ENSP00000390600.2 Q9Y5Y9
SCN10AENST00000643924.1 linkc.2842G>A p.Val948Met missense_variant 16/27 ENSP00000495595.1 A0A2R8Y6J6
SCN10AENST00000655275.1 linkc.2869G>A p.Val957Met missense_variant 17/28 ENSP00000499510.1 A0A590UJM0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461758
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000264
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2022This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 948 of the SCN10A protein (p.Val948Met). This variant is not present in population databases (gnomAD no frequency). 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: 532079). 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 submitterclinical testingAmbry GeneticsAug 26, 2024The c.2842G>A (p.V948M) alteration is located in exon 16 (coding exon 16) of the SCN10A gene. This alteration results from a G to A substitution at nucleotide position 2842, causing the valine (V) at amino acid position 948 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.048
T;.;T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.51
.;T;T;T
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
0.69
N;.;N;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.58
N;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.13
T;.;.;.
Sift4G
Benign
0.14
T;.;.;.
Polyphen
0.055
B;.;B;.
Vest4
0.057
MutPred
0.67
Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);
MVP
0.62
MPC
0.076
ClinPred
0.068
T
GERP RS
2.5
Varity_R
0.047
gMVP
0.093

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: rs145694222; hg19: chr3-38768342; API