rs141207048

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000449082.3(SCN10A):c.41G>T(p.Arg14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,936 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. R14H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 6 hom. )

Consequence

SCN10A
ENST00000449082.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.530

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028188914).

BP6

Variant 3-38793970-C-A is Benign according to our data. Variant chr3-38793970-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 414623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38793970-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.41G>T	p.Arg14Leu	missense_variant	2/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SCN10A	ENST00000449082.3 linkuse as main transcript	c.41G>T	p.Arg14Leu	missense_variant	2/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.41G>T	p.Arg14Leu	missense_variant	2/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.41G>T	p.Arg14Leu	missense_variant	1/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00194

AC:

486

AN:

250810

Hom.:

AF XY:

0.00174

AC XY:

236

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00954

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00279

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00274

AC:

3999

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

1914

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00907

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00308

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152274

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00297

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.00173

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00193

AC:

234

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN10A: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 24998131, 25691686, 25691538, 26733327, 28589536, 27761160, 27200363, 27446933, 24998132, 27272739, 28407228, 27711072, 30662450, 30821013, 31539150) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 28, 2024

- -

Brugada syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Episodic pain syndrome, familial, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2019

This alteration is classified as likely 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

0.20

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;D;.

Eigen

Benign

0.11

Eigen_PC

Benign

-0.068

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.86

.;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.028

T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.5

M;.;M;.

MutationTaster

Benign

0.90

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.8

D;.;.;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0050

D;.;.;.

Sift4G

Uncertain

0.034

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.54

MVP

0.87

MPC

0.26

ClinPred

0.047

GERP RS

2.3

Varity_R

0.38

gMVP

0.64

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