3-38755819-G-A

Position:

chr3-38755819-G-A

Variant summary

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

The NM_006514.4(SCN10A):c.1430C>T(p.Pro477Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.712

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=0.03691721).

BP6

Variant 3-38755819-G-A is Benign according to our data. Variant chr3-38755819-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38755819-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.1430C>T	p.Pro477Leu	missense_variant	11/28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 linkuse as main transcript	c.1430C>T	p.Pro477Leu	missense_variant	11/28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 linkuse as main transcript	c.1430C>T	p.Pro477Leu	missense_variant	10/27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 linkuse as main transcript	c.1457C>T	p.Pro486Leu	missense_variant	11/28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000517

AC:

130

AN:

251480

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000914

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000789

AC:

1153

AN:

1461712

Hom.:

Cov.:

AF XY:

0.000810

AC XY:

589

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000936

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000381

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000752

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, 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	Sep 24, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Episodic pain syndrome, familial, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 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

0.065

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.0

DANN

Benign

0.60

DEOGEN2

Uncertain

0.47

T;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.67

.;T;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.2

M;.;M;.

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.3

D;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.074

T;.;.;.

Sift4G

Benign

0.45

T;.;.;.

Polyphen

0.0020

B;.;B;.

Vest4

0.10

MVP

0.44

MPC

0.068

ClinPred

0.025

GERP RS

0.15

Varity_R

0.055

gMVP

0.23

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