rs138413438

Variant summary

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

The NM_006514.4(SCN10A):c.2972C>T(p.Pro991Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,612,904 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P991P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.43

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=0.08891508).

BP6

Variant 3-38726721-G-A is Benign according to our data. Variant chr3-38726721-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38726721-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.2972C>T	p.Pro991Leu	missense_variant	17/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN10A	ENST00000449082.3 linkuse as main transcript	c.2972C>T	p.Pro991Leu	missense_variant	17/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.2999C>T	p.Pro1000Leu	missense_variant	17/28
SCN10A	ENST00000643924.1 linkuse as main transcript	c.2972C>T	p.Pro991Leu	missense_variant	16/27			A1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000964

AC:

242

AN:

250924

Hom.:

AF XY:

0.00103

AC XY:

139

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00125

AC:

1830

AN:

1460624

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

894

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.000879

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152280

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000889

AC:

108

EpiCase

AF:

0.00202

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2017

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. -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

SCN10A: BS1, BS2 -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 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

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;D;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.71

M_CAP

Benign

0.051

MetaRNN

Benign

0.089

T;T;T;T

MetaSVM

Uncertain

-0.080

MutationAssessor

Uncertain

2.2

M;.;M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-7.8

D;.;.;.

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Uncertain

0.0050

D;.;.;.

Polyphen

0.98

D;.;D;.

Vest4

0.33

MVP

0.87

MPC

0.29

ClinPred

0.075

GERP RS

3.9

Varity_R

0.45

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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