rs74717885

Variant names:

Variant summary

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

The NM_006514.4(SCN10A):c.618A>G(p.Ile206Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,802 control chromosomes in the GnomAD database, including 716 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 0.016 ( 73 hom., cov: 32)

Exomes 𝑓: 0.019 ( 643 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.537

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=0.0017729998).

BP6

Variant 3-38763578-T-C is Benign according to our data. Variant chr3-38763578-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 381545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38763578-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.618A>G	p.Ile206Met	missense_variant	Exon 6 of 28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 link	c.618A>G	p.Ile206Met	missense_variant	Exon 6 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.618A>G	p.Ile206Met	missense_variant	Exon 5 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.618A>G	p.Ile206Met	missense_variant	Exon 6 of 28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2437

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.0381

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0255

AC:

6413

AN:

251314

Hom.:

258

AF XY:

0.0267

AC XY:

3629

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00714

Gnomad ASJ exome

AF:

0.0220

Gnomad EAS exome

AF:

0.151

Gnomad SAS exome

AF:

0.0357

Gnomad FIN exome

AF:

0.00648

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0192

AC:

28084

AN:

1461466

Hom.:

643

Cov.:

AF XY:

0.0200

AC XY:

14515

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00747

Gnomad4 ASJ exome

AF:

0.0209

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.0385

Gnomad4 FIN exome

AF:

0.00691

Gnomad4 NFE exome

AF:

0.0150

Gnomad4 OTH exome

AF:

0.0222

GnomAD4 genome

AF:

0.0160

AC:

2436

AN:

152336

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.0383

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0197

Hom.:

114

Bravo

AF:

0.0159

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0256

AC:

3106

Asia WGS

AF:

0.0660

AC:

228

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0192

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 29, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brugada syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype

Benign:1

Mar 04, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.078

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.58

D;.;D;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.50

.;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.2

L;.;L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;.;.;.

REVEL

Benign

0.20

Sift

Uncertain

0.010

D;.;.;.

Sift4G

Benign

0.20

T;.;.;.

Polyphen

0.0080

B;.;B;.

Vest4

0.077

MPC

0.066

ClinPred

0.0079

GERP RS

-0.84

Varity_R

0.14

gMVP

0.47

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