rs148663098

Variant summary

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

The NM_006514.4(SCN10A):​c.410C>T​(p.Thr137Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,610,698 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T137T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.01
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07856923).
BS2
High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN10ANM_006514.4 linkuse as main transcriptc.410C>T p.Thr137Met missense_variant 4/28 ENST00000449082.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN10AENST00000449082.3 linkuse as main transcriptc.410C>T p.Thr137Met missense_variant 4/281 NM_006514.4 P4
SCN10AENST00000655275.1 linkuse as main transcriptc.410C>T p.Thr137Met missense_variant 4/28
SCN10AENST00000643924.1 linkuse as main transcriptc.410C>T p.Thr137Met missense_variant 3/27 A1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152108
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250726
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135514
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1458590
Hom.:
0
Cov.:
28
AF XY:
0.00000964
AC XY:
7
AN XY:
725836
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
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:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-- -
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 19, 2022This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 137 of the SCN10A protein (p.Thr137Met). This variant is present in population databases (rs148663098, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 24998131). ClinVar contains an entry for this variant (Variation ID: 463256). 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 26, 2020Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 463256; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24998131, 28407228, 30821013) -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 23, 2023The p.T137M variant (also known as c.410C>T), located in coding exon 3 of the SCN10A gene, results from a C to T substitution at nucleotide position 410. The threonine at codon 137 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort, as well as an autism spectrum disorder whole exome sequencing cohort (Hu D et al. J Am Coll Cardiol, 2014 Jul;64:66-79; Abou Ziki MD et al. Clin Genet, 2018 04;93:741-751; Patowary A et al. Transl Psychiatry, 2019 01;9:4). This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
19
DANN
Benign
0.057
DEOGEN2
Benign
0.36
T;.;T;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.91
.;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.079
T;T;T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
-1.5
N;.;N;.
MutationTaster
Benign
0.97
D
PrimateAI
Benign
0.36
T
PROVEAN
Benign
4.1
N;.;.;.
REVEL
Uncertain
0.32
Sift
Benign
1.0
T;.;.;.
Sift4G
Benign
1.0
T;.;.;.
Polyphen
0.022
B;.;B;.
Vest4
0.35
MVP
0.84
MPC
0.063
ClinPred
0.15
T
GERP RS
3.3
Varity_R
0.040
gMVP
0.30

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: rs148663098; hg19: chr3-38830507; API