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3-38697400-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006514.4(SCN10A):c.5820A>G(p.Ile1940Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.68
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 -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05333233).
BP6
Variant 3-38697400-T-C is Benign according to our data. Variant chr3-38697400-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 834159.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN10ANM_006514.4 linkuse as main transcriptc.5820A>G p.Ile1940Met missense_variant 28/28 ENST00000449082.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN10AENST00000449082.3 linkuse as main transcriptc.5820A>G p.Ile1940Met missense_variant 28/281 NM_006514.4 P4
SCN10AENST00000655275.1 linkuse as main transcriptc.5844A>G p.Ile1948Met missense_variant 28/28
SCN10AENST00000643924.1 linkuse as main transcriptc.5817A>G p.Ile1939Met missense_variant 27/27 A1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 15, 2019In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN10A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 1940 of the SCN10A protein (p.Ile1940Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 13, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
Cadd
Benign
0.55
Dann
Benign
0.81
DEOGEN2
Benign
0.041
T;.;T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.020
N
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.053
T;T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
0.0
N;.;N;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
1.0
N;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.23
T;.;.;.
Sift4G
Benign
0.23
T;.;.;.
Polyphen
0.0010
B;.;B;.
Vest4
0.036
MutPred
0.19
Gain of glycosylation at S1937 (P = 0.0193);Gain of glycosylation at S1937 (P = 0.0193);Gain of glycosylation at S1937 (P = 0.0193);.;
MVP
0.44
MPC
0.060
ClinPred
0.041
T
GERP RS
-2.5
Varity_R
0.045
gMVP
0.31

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: rs2063100815; hg19: chr3-38738891; API