rs6795970

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3218T>C(p.Val1073Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,594,466 control chromosomes in the GnomAD database, including 318,682 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1073I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.70 ( 38763 hom., cov: 32)

Exomes 𝑓: 0.62 ( 279919 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.04

Publications

157 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=7.03869E-7).

BP6

Variant 3-38725184-A-G is Benign according to our data. Variant chr3-38725184-A-G is described in ClinVar as Benign. ClinVar VariationId is 259996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.3218T>C	p.Val1073Ala	missense_variant	Exon 18 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN10A	ENST00000449082.3 link	c.3218T>C	p.Val1073Ala	missense_variant	Exon 18 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1 link	c.3215T>C	p.Val1072Ala	missense_variant	Exon 17 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1 link	c.3242T>C	p.Val1081Ala	missense_variant	Exon 18 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes

AF:

0.700

AC:

106402

AN:

151966

Hom.:

38689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.550

Gnomad AMR

AF:

0.677

Gnomad ASJ

AF:

0.588

Gnomad EAS

AF:

0.850

Gnomad SAS

AF:

0.664

Gnomad FIN

AF:

0.543

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.605

Gnomad OTH

AF:

0.653

GnomAD2 exomes

AF:

0.652

AC:

161934

AN:

248186

AF XY:

0.644

show subpopulations

Gnomad AFR exome

AF:

0.911

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.581

Gnomad EAS exome

AF:

0.848

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.603

Gnomad OTH exome

AF:

0.620

GnomAD4 exome

AF:

0.619

AC:

893149

AN:

1442382

Hom.:

279919

Cov.:

AF XY:

0.618

AC XY:

442210

AN XY:

715412

show subpopulations

African (AFR)

AF:

0.917

AC:

30453

AN:

33202

American (AMR)

AF:

0.686

AC:

30267

AN:

44098

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

15049

AN:

25840

East Asian (EAS)

AF:

0.851

AC:

33500

AN:

39346

South Asian (SAS)

AF:

0.643

AC:

54279

AN:

84368

European-Finnish (FIN)

AF:

0.549

AC:

29172

AN:

53116

Middle Eastern (MID)

AF:

0.546

AC:

3076

AN:

5634

European-Non Finnish (NFE)

AF:

0.601

AC:

659788

AN:

1097380

Other (OTH)

AF:

0.632

AC:

37565

AN:

59398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

15315

30630

45946

61261

76576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18306

36612

54918

73224

91530

<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:

0.701

AC:

106542

AN:

152084

Hom.:

38763

Cov.:

AF XY:

0.699

AC XY:

51984

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.907

AC:

37664

AN:

41512

American (AMR)

AF:

0.678

AC:

10361

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

2041

AN:

3470

East Asian (EAS)

AF:

0.851

AC:

4402

AN:

5170

South Asian (SAS)

AF:

0.664

AC:

3197

AN:

4812

European-Finnish (FIN)

AF:

0.543

AC:

5733

AN:

10562

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.605

AC:

41082

AN:

67954

Other (OTH)

AF:

0.655

AC:

1383

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1533

3066

4600

6133

7666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.636

Hom.:

150645

Bravo

AF:

0.719

TwinsUK

AF:

0.604

AC:

2239

ALSPAC

AF:

0.596

AC:

2297

ESP6500AA

AF:

0.899

AC:

3961

ESP6500EA

AF:

0.602

AC:

5176

ExAC

AF:

0.657

AC:

79802

Asia WGS

AF:

0.771

AC:

2681

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 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. -

Jun 10, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2023

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

- -

Brugada syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic pain syndrome, familial, 2

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 03, 2018

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

0.064

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.66

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.031

T;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.060

.;T;T;T

MetaRNN

Benign

7.0e-7

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

N;.;N;.

PhyloP100

-1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

0.51

N;.;.;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.;.;.

Sift4G

Benign

1.0

T;.;.;.

Polyphen

0.0

B;.;B;.

Vest4

0.0060

MPC

0.070

ClinPred

0.00070

GERP RS

-4.6

Varity_R

0.024

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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