rs6795970

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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=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 id is 259996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38725184-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.3218T>C	p.Val1073Ala	missense_variant	18/28	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.3218T>C	p.Val1073Ala	missense_variant	18/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.3242T>C	p.Val1081Ala	missense_variant	18/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.3215T>C	p.Val1072Ala	missense_variant	17/27			ENSP00000495595	A1

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

GnomAD3 exomes

AF:

0.652

AC:

161934

AN:

248186

Hom.:

54207

AF XY:

0.644

AC XY:

86354

AN XY:

134142

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 SAS exome

AF:

0.645

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

Gnomad4 AFR exome

AF:

0.917

Gnomad4 AMR exome

AF:

0.686

Gnomad4 ASJ exome

AF:

0.582

Gnomad4 EAS exome

AF:

0.851

Gnomad4 SAS exome

AF:

0.643

Gnomad4 FIN exome

AF:

0.549

Gnomad4 NFE exome

AF:

0.601

Gnomad4 OTH exome

AF:

0.632

GnomAD4 genome

AF:

0.701

AC:

106542

AN:

152084

Hom.:

38763

Cov.:

AF XY:

0.699

AC XY:

51984

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.907

Gnomad4 AMR

AF:

0.678

Gnomad4 ASJ

AF:

0.588

Gnomad4 EAS

AF:

0.851

Gnomad4 SAS

AF:

0.664

Gnomad4 FIN

AF:

0.543

Gnomad4 NFE

AF:

0.605

Gnomad4 OTH

AF:

0.655

Alfa

AF:

0.622

Hom.:

73971

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 10, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Episodic pain syndrome, familial, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 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

0.064

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.66

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;.

MutationTaster

Benign

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

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

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