3-38756826-C-T

Position:

chr3-38756826-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_006514.4(SCN10A):c.1138G>A(p.Val380Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:3B:5

Conservation

PhyloP100: 2.65

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.116723776).

BP6

Variant 3-38756826-C-T is Benign according to our data. Variant chr3-38756826-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.1138G>A	p.Val380Ile	missense_variant	10/28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 link	c.1138G>A	p.Val380Ile	missense_variant	10/28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.1138G>A	p.Val380Ile	missense_variant	9/27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.1165G>A	p.Val389Ile	missense_variant	10/28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000521

AC:

131

AN:

251340

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000454

AC:

664

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000451

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000539

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000788

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

SCN10A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

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

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Episodic pain syndrome, familial, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 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

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D;D;D

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

L;.;L;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.92

N;.;.;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.029

D;.;.;.

Sift4G

Benign

0.30

T;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.43

MVP

0.85

MPC

0.30

ClinPred

0.043

GERP RS

5.3

Varity_R

0.19

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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