chr3-38750172-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006514.4(SCN10A):c.1768G>A(p.Gly590Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,609,618 control chromosomes in the GnomAD database, including 6 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 (★★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.78

Publications

2 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062061846).

BP6

Variant 3-38750172-C-T is Benign according to our data. Variant chr3-38750172-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 530 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.1768G>A	p.Gly590Arg	missense_variant	Exon 13 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.1768G>A	p.Gly590Arg	missense_variant	Exon 13 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.1768G>A	p.Gly590Arg	missense_variant	Exon 12 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.1795G>A	p.Gly599Arg	missense_variant	Exon 13 of 28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00103

AC:

257

AN:

250256

AF XY:

0.000902

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.00132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.000303

AC:

441

AN:

1457276

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

206

AN XY:

725242

show subpopulations

African (AFR)

AF:

0.00961

AC:

321

AN:

33390

American (AMR)

AF:

0.00141

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

85810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1108304

Other (OTH)

AF:

0.000697

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00348

AC:

530

AN:

152342

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0119

AC:

496

AN:

41582

American (AMR)

AF:

0.00144

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00118

Hom.:

Bravo

AF:

0.00386

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 10, 2017

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. -

May 26, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SCN10A-related disorder

Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Episodic pain syndrome, familial, 2

Benign:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.087

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.042

T;.;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.72

.;T;T;T

MetaRNN

Benign

0.0062

T;T;T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

-0.85

N;.;N;.

PhyloP100

1.8

PrimateAI

Benign

0.41

PROVEAN

Benign

0.65

N;.;.;.

REVEL

Benign

0.24

Sift

Benign

0.81

T;.;.;.

Sift4G

Benign

0.38

T;.;.;.

Polyphen

0.73

P;.;P;.

Vest4

0.38

MutPred

0.24

Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);

MVP

0.64

MPC

0.14

ClinPred

0.043

GERP RS

3.6

Varity_R

0.044

gMVP

0.43

Mutation Taster

=96/4

polymorphism

(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