rs57326399

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000449082.3(SCN10A):c.2884A>G(p.Ile962Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,611,336 control chromosomes in the GnomAD database, including 50,977 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3920 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47057 hom. )

Consequence

SCN10A
ENST00000449082.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.434

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023588836).

BP6

Variant 3-38726809-T-C is Benign according to our data. Variant chr3-38726809-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38726809-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.2884A>G	p.Ile962Val	missense_variant	17/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SCN10A	ENST00000449082.3 linkuse as main transcript	c.2884A>G	p.Ile962Val	missense_variant	17/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.2911A>G	p.Ile971Val	missense_variant	17/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.2884A>G	p.Ile962Val	missense_variant	16/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32261

AN:

152016

Hom.:

3920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.208

GnomAD3 exomes

AF:

0.237

AC:

59575

AN:

251024

Hom.:

7853

AF XY:

0.243

AC XY:

32923

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.388

Gnomad SAS exome

AF:

0.229

Gnomad FIN exome

AF:

0.269

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.239

GnomAD4 exome

AF:

0.249

AC:

363364

AN:

1459202

Hom.:

47057

Cov.:

AF XY:

0.249

AC XY:

180778

AN XY:

725238

show subpopulations

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.335

Gnomad4 EAS exome

AF:

0.425

Gnomad4 SAS exome

AF:

0.235

Gnomad4 FIN exome

AF:

0.270

Gnomad4 NFE exome

AF:

0.251

Gnomad4 OTH exome

AF:

0.241

GnomAD4 genome

AF:

0.212

AC:

32263

AN:

152134

Hom.:

3920

Cov.:

AF XY:

0.214

AC XY:

15908

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.143

Gnomad4 ASJ

AF:

0.344

Gnomad4 EAS

AF:

0.403

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.269

Gnomad4 NFE

AF:

0.257

Gnomad4 OTH

AF:

0.206

Alfa

AF:

0.254

Hom.:

7928

Bravo

AF:

0.198

TwinsUK

AF:

0.249

AC:

925

ALSPAC

AF:

0.242

AC:

934

ESP6500AA

AF:

0.109

AC:

482

ESP6500EA

AF:

0.262

AC:

2253

ExAC

AF:

0.241

AC:

29240

Asia WGS

AF:

0.268

AC:

935

AN:

3478

EpiCase

AF:

0.246

EpiControl

AF:

0.249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Episodic pain syndrome, familial, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

This alteration is classified as 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

0.082

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

4.4

DANN

Benign

0.34

DEOGEN2

Benign

0.041

T;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.17

.;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.87

L;.;L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.18

N;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.12

T;.;.;.

Sift4G

Benign

0.53

T;.;.;.

Polyphen

0.44

B;.;B;.

Vest4

0.028

MPC

0.054

ClinPred

0.0097

GERP RS

-4.2

Varity_R

0.030

gMVP

0.13

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