rs143744796

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_006514.4(SCN10A):c.3417G>C(p.Trp1139Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.08

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]

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

BS2

High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.3417G>C	p.Trp1139Cys	missense_variant	20/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN10A	ENST00000449082.3 linkuse as main transcript	c.3417G>C	p.Trp1139Cys	missense_variant	20/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.3441G>C	p.Trp1147Cys	missense_variant	20/28
SCN10A	ENST00000643924.1 linkuse as main transcript	c.3414G>C	p.Trp1138Cys	missense_variant	19/27			A1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000954

AC:

AN:

251452

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

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:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000107

AC:

157

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

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:

0.000118

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1139 of the SCN10A protein (p.Trp1139Cys). This variant is present in population databases (rs143744796, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome or arrhythmogenic right ventricular cardiomyopathy (PMID: 25691538, 26733327). ClinVar contains an entry for this variant (Variation ID: 532064). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Episodic pain syndrome, familial, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2023

Reported in association with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy (Behr et al., 2015; Te Riele et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26733327, 25691538) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2020

This 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

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.32

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.6

M;.;M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-12

D;.;.;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Uncertain

0.028

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.77

MutPred

0.84

Gain of glycosylation at T1144 (P = 0.0221);Gain of glycosylation at T1144 (P = 0.0221);Gain of glycosylation at T1144 (P = 0.0221);.;

MVP

0.82

MPC

0.46

ClinPred

0.92

GERP RS

4.3

Varity_R

0.76

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over