3-38698354-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006514.4(SCN10A):c.4866T>C(p.Ser1622Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,614,070 control chromosomes in the GnomAD database, including 675,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66000 hom., cov: 30)

Exomes 𝑓: 0.91 ( 609773 hom. )

Consequence

SCN10A
NM_006514.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.831

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 3-38698354-A-G is Benign according to our data. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698354-A-G is described in CliVar as Benign. Clinvar id is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.831 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.4866T>C	p.Ser1622Ser	synonymous_variant	Exon 28 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.4866T>C	p.Ser1622Ser	synonymous_variant	Exon 28 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.4863T>C	p.Ser1621Ser	synonymous_variant	Exon 27 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.4890T>C	p.Ser1630Ser	synonymous_variant	Exon 28 of 28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.931

AC:

141560

AN:

152060

Hom.:

65940

Cov.:

show subpopulations

Gnomad AFR

AF:

0.961

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.921

Gnomad ASJ

AF:

0.941

Gnomad EAS

AF:

0.963

Gnomad SAS

AF:

0.876

Gnomad FIN

AF:

0.936

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.915

Gnomad OTH

AF:

0.932

GnomAD2 exomes

AF:

0.920

AC:

231246

AN:

251356

AF XY:

0.917

show subpopulations

Gnomad AFR exome

AF:

0.961

Gnomad AMR exome

AF:

0.914

Gnomad ASJ exome

AF:

0.943

Gnomad EAS exome

AF:

0.969

Gnomad FIN exome

AF:

0.935

Gnomad NFE exome

AF:

0.916

Gnomad OTH exome

AF:

0.922

GnomAD4 exome

AF:

0.913

AC:

1334834

AN:

1461892

Hom.:

609773

Cov.:

AF XY:

0.912

AC XY:

663209

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.962

AC:

32193

AN:

33480

American (AMR)

AF:

0.916

AC:

40986

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.943

AC:

24658

AN:

26136

East Asian (EAS)

AF:

0.963

AC:

38217

AN:

39700

South Asian (SAS)

AF:

0.879

AC:

75840

AN:

86258

European-Finnish (FIN)

AF:

0.931

AC:

49730

AN:

53420

Middle Eastern (MID)

AF:

0.951

AC:

5487

AN:

5768

European-Non Finnish (NFE)

AF:

0.911

AC:

1012501

AN:

1112012

Other (OTH)

AF:

0.914

AC:

55222

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8542

17083

25625

34166

42708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21492

42984

64476

85968

107460

<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:

0.931

AC:

141679

AN:

152178

Hom.:

66000

Cov.:

AF XY:

0.932

AC XY:

69290

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.961

AC:

39886

AN:

41516

American (AMR)

AF:

0.921

AC:

14084

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.941

AC:

3265

AN:

3468

East Asian (EAS)

AF:

0.963

AC:

4966

AN:

5158

South Asian (SAS)

AF:

0.876

AC:

4215

AN:

4810

European-Finnish (FIN)

AF:

0.936

AC:

9926

AN:

10606

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.915

AC:

62251

AN:

68014

Other (OTH)

AF:

0.933

AC:

1967

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

493

985

1478

1970

2463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.923

Hom.:

170006

Bravo

AF:

0.932

Asia WGS

AF:

0.905

AC:

3150

AN:

3478

EpiCase

AF:

0.917

EpiControl

AF:

0.922

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Sep 06, 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

- -

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.2

(source)

DANN

Benign

0.73

PhyloP100

0.83

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