rs145694222

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006514.4(SCN10A):c.2842G>C(p.Val948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,614,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V948M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.346

Publications

5 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038193822).

BP6

Variant 3-38726851-C-G is Benign according to our data. Variant chr3-38726851-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407748.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 64 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.2842G>C	p.Val948Leu	missense_variant	Exon 17 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.2842G>C	p.Val948Leu	missense_variant	Exon 17 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.2842G>C	p.Val948Leu	missense_variant	Exon 16 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.2869G>C	p.Val957Leu	missense_variant	Exon 17 of 28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000691

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000490

AC:

123

AN:

251218

AF XY:

0.000516

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000899

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000841

AC:

1230

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00107

AC:

1192

AN:

1111902

Other (OTH)

AF:

0.000381

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000420

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41562

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000628

Hom.:

Bravo

AF:

0.000533

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 25, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28078312, 26220970) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN10A: BP4, BS1 -

Episodic pain syndrome, familial, 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Benign:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 20, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.040

T;.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.43

.;T;T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.038

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.090

N;.;N;.

PhyloP100

0.35

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.28

N;.;.;.

REVEL

Benign

0.16

Sift

Benign

0.29

T;.;.;.

Sift4G

Benign

0.42

T;.;.;.

Polyphen

0.12

B;.;B;.

Vest4

0.063

MutPred

0.70

Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);

MVP

0.62

MPC

0.061

ClinPred

0.0023

GERP RS

2.5

Varity_R

0.061

gMVP

0.11

Mutation Taster

=94/6

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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rs145694222

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