rs553784643

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006514.4(SCN10A):c.1715C>T(p.Pro572Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,571,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.706

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.080750346).

BP6

Variant 3-38752259-G-A is Benign according to our data. Variant chr3-38752259-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407749.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.1715C>T	p.Pro572Leu	missense_variant	12/28	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.1715C>T	p.Pro572Leu	missense_variant	12/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.1742C>T	p.Pro581Leu	missense_variant	12/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.1715C>T	p.Pro572Leu	missense_variant	11/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000593

AC:

AN:

219102

Hom.:

AF XY:

0.0000422

AC XY:

AN XY:

118420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000676

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000253

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000596

Gnomad OTH exome

AF:

0.000197

GnomAD4 exome

AF:

0.0000324

AC:

AN:

1419916

Hom.:

Cov.:

AF XY:

0.0000256

AC XY:

AN XY:

703760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000495

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000160

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000312

Gnomad4 OTH exome

AF:

0.0000513

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000354

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2018

A variant of uncertain significance has been identified in the SCN10A gene. The P572L variant has not been published as pathogenic or been reported as benign to our knowledge. It is classified as a variant of uncertain significance in ClinVar by another clinical laboratory (SCV000547178.2; Landrum et al., 2016). This variant is observed at a global allele frequency of 13/214918 (0.006%) alleles in large population cohorts, including 4/14804 (0.03%) alleles from individuals of East Asian ancestry (Lek et al., 2016). The P572L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 572 of the SCN10A protein (p.Pro572Leu). This variant is present in population databases (rs553784643, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 407749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN10A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2023

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

0.050

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

5.0

DANN

Benign

0.24

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00039

LIST_S2

Benign

0.35

.;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.081

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.17

N;.;N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.68

N;.;.;.

REVEL

Benign

0.24

Sift

Benign

0.31

T;.;.;.

Sift4G

Benign

0.44

T;.;.;.

Polyphen

0.0

B;.;B;.

Vest4

0.11

MVP

0.43

MPC

0.060

ClinPred

0.019

GERP RS

2.9

Varity_R

0.030

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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