rs73062575

Positions:

chr3-38725269-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000449082.3(SCN10A):c.3133C>A(p.Pro1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,600,220 control chromosomes in the GnomAD database, including 653 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1045L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 33)

Exomes 𝑓: 0.026 ( 628 hom. )

Consequence

SCN10A
ENST00000449082.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0450

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=0.003993094).

BP6

Variant 3-38725269-G-T is Benign according to our data. Variant chr3-38725269-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 240667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38725269-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2636/152326) while in subpopulation NFE AF= 0.0285 (1940/68036). AF 95% confidence interval is 0.0275. There are 25 homozygotes in gnomad4. There are 1160 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2636 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.3133C>A	p.Pro1045Thr	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.3133C>A	p.Pro1045Thr	missense_variant	18/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.3157C>A	p.Pro1053Thr	missense_variant	18/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.3130C>A	p.Pro1044Thr	missense_variant	17/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2635

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0155

AC:

3853

AN:

248330

Hom.:

AF XY:

0.0153

AC XY:

2059

AN XY:

134212

show subpopulations

Gnomad AFR exome

AF:

0.00440

Gnomad AMR exome

AF:

0.00801

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00426

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.0242

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0259

AC:

37530

AN:

1447894

Hom.:

628

Cov.:

AF XY:

0.0253

AC XY:

18168

AN XY:

719370

show subpopulations

Gnomad4 AFR exome

AF:

0.00340

Gnomad4 AMR exome

AF:

0.00752

Gnomad4 ASJ exome

AF:

0.0219

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00402

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.0309

Gnomad4 OTH exome

AF:

0.0232

GnomAD4 genome

AF:

0.0173

AC:

2636

AN:

152326

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1160

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0285

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0245

Hom.:

Bravo

AF:

0.0167

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0317

AC:

273

ExAC

AF:

0.0147

AC:

1785

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2023	- -

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

- -

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

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.048

T;.;T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.51

.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.0

L;.;L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.74

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.12

T;.;.;.

Sift4G

Benign

0.33

T;.;.;.

Polyphen

0.10

B;.;B;.

Vest4

0.080

MPC

0.069

ClinPred

0.0014

GERP RS

2.5

Varity_R

0.053

gMVP

0.27

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