3-38697615-G-A

Position:

chr3-38697615-G-A

Variant summary

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

The ENST00000449082.3(SCN10A):c.5605C>T(p.Arg1869Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,614,112 control chromosomes in the GnomAD database, including 9 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. R1869H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

SCN10A
ENST00000449082.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.22

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=0.013748288).

BP6

Variant 3-38697615-G-A is Benign according to our data. Variant chr3-38697615-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 420024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38697615-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.5605C>T	p.Arg1869Cys	missense_variant	28/28	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.5605C>T	p.Arg1869Cys	missense_variant	28/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.5629C>T	p.Arg1877Cys	missense_variant	28/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.5602C>T	p.Arg1868Cys	missense_variant	27/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000999

AC:

251

AN:

251126

Hom.:

AF XY:

0.000899

AC XY:

122

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.00158

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000527

AC:

770

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

405

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0166

Gnomad4 EAS exome

AF:

0.00156

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.000584

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000807

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SCN10A: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	This variant is associated with the following publications: (PMID: 27711072, 26733327, 24998131, 29016797, 30821013, 32948286) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2019

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

0.11

BayesDel_addAF

Benign

-0.00030

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

.;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.;M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.8

D;.;.;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.61

MVP

0.99

MPC

0.33

ClinPred

0.081

GERP RS

5.1

Varity_R

0.58

gMVP

0.61

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