rs74717885

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I206V) has been classified as Uncertain significance.

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

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
episodic pain syndrome, familial, 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 381545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.0255

AC:

6413

AN:

251314

AF XY:

0.0267

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 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

African (AFR)

AF:

0.00245

AC:

AN:

33474

American (AMR)

AF:

0.00747

AC:

334

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

545

AN:

26134

East Asian (EAS)

AF:

0.134

AC:

5304

AN:

39696

South Asian (SAS)

AF:

0.0385

AC:

3319

AN:

86236

European-Finnish (FIN)

AF:

0.00691

AC:

369

AN:

53378

Middle Eastern (MID)

AF:

0.0246

AC:

142

AN:

5766

European-Non Finnish (NFE)

AF:

0.0150

AC:

16651

AN:

1111688

Other (OTH)

AF:

0.0222

AC:

1338

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1250

2500

3751

5001

6251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

702

1404

2106

2808

3510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2436

AN:

152336

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41572

American (AMR)

AF:

0.0104

AC:

159

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3472

East Asian (EAS)

AF:

0.146

AC:

755

AN:

5188

South Asian (SAS)

AF:

0.0383

AC:

185

AN:

4824

European-Finnish (FIN)

AF:

0.00593

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0152

AC:

1037

AN:

68034

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0186

Hom.:

148

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

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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. -

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

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

(source)

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;.

PhyloP100

-0.54

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

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over