chr3-38723507-A-G

Position:

chr3-38723507-A-G

Variant summary

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

The NM_006514.4(SCN10A):c.3275T>C(p.Leu1092Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,611,844 control chromosomes in the GnomAD database, including 51,330 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 0.22 ( 4103 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47227 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.776

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=0.0020908415).

BP6

Variant 3-38723507-A-G is Benign according to our data. Variant chr3-38723507-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38723507-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.3275T>C	p.Leu1092Pro	missense_variant	19/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN10A	ENST00000449082.3 linkuse as main transcript	c.3275T>C	p.Leu1092Pro	missense_variant	19/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.3299T>C	p.Leu1100Pro	missense_variant	19/28
SCN10A	ENST00000643924.1 linkuse as main transcript	c.3272T>C	p.Leu1091Pro	missense_variant	18/27			A1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33587

AN:

152066

Hom.:

4103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.373

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.216

GnomAD3 exomes

AF:

0.240

AC:

58530

AN:

243924

Hom.:

7572

AF XY:

0.245

AC XY:

32303

AN XY:

132000

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.389

Gnomad SAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.250

AC:

364980

AN:

1459660

Hom.:

47227

Cov.:

AF XY:

0.250

AC XY:

181556

AN XY:

725990

show subpopulations

Gnomad4 AFR exome

AF:

0.130

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.332

Gnomad4 EAS exome

AF:

0.437

Gnomad4 SAS exome

AF:

0.233

Gnomad4 FIN exome

AF:

0.273

Gnomad4 NFE exome

AF:

0.251

Gnomad4 OTH exome

AF:

0.244

GnomAD4 genome

AF:

0.221

AC:

33596

AN:

152184

Hom.:

4103

Cov.:

AF XY:

0.223

AC XY:

16583

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.149

Gnomad4 ASJ

AF:

0.341

Gnomad4 EAS

AF:

0.403

Gnomad4 SAS

AF:

0.241

Gnomad4 FIN

AF:

0.273

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.214

Alfa

AF:

0.246

Hom.:

12059

Bravo

AF:

0.209

TwinsUK

AF:

0.250

AC:

926

ALSPAC

AF:

0.241

AC:

928

ESP6500AA

AF:

0.142

AC:

625

ESP6500EA

AF:

0.260

AC:

2236

ExAC

AF:

0.241

AC:

29298

Asia WGS

AF:

0.272

AC:

946

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Episodic pain syndrome, familial, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

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

0.046

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.036

T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.24

.;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.72

N;.;N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

3.2

N;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.60

T;.;.;.

Sift4G

Benign

0.41

T;.;.;.

Polyphen

0.0

B;.;B;.

Vest4

0.013

MPC

0.092

ClinPred

0.0018

GERP RS

-0.53

Varity_R

0.087

gMVP

0.40

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