rs199973777

Positions:

chr3-38792131-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP3BP4_ModerateBP6_Very_StrongBS2

The ENST00000449082.3(SCN10A):c.308G>A(p.Arg103Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,826 control chromosomes in the GnomAD database, including 2 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. R103W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

SCN10A
ENST00000449082.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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 -13 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.21418944).

BP6

Variant 3-38792131-C-T is Benign according to our data. Variant chr3-38792131-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 532134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38792131-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.308G>A	p.Arg103Gln	missense_variant	3/28	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.308G>A	p.Arg103Gln	missense_variant	3/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.308G>A	p.Arg103Gln	missense_variant	3/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.308G>A	p.Arg103Gln	missense_variant	2/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

251020

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1461586

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00182

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000368

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000687

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

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

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;.;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;M;.

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

D;.;.;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.61

MVP

0.97

MPC

0.40

ClinPred

0.33

GERP RS

4.2

Varity_R

0.68

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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