rs202192818

Positions:

chr3-38771406-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_006514.4(SCN10A):c.472T>G(p.Tyr158Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000398 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense, splice_region

Scores

Splicing: ADA: 0.0004975

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 5.23

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

BS2

High AC in GnomAd4 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.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28	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.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1 linkuse as main transcript	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28			ENSP00000499510
SCN10A	ENST00000643924.1 linkuse as main transcript	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	4/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251360

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000408

AC:

596

AN:

1461462

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

266

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000302

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000443

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2024	Reported in individuals with atrial fibrillation, arrhythmogenic right ventricular cardiomyopathy (ARVC), AV nodal reentrant tachycardia, sudden cardiac arrest, or diabetic peripheral neuropathy (DPN) many of whom also harbored the p.(R814H) variant in the SCN10A gene in either cis or unknown configuration (PMID: 25053638, 25691686, 26733327, 28407228, 29396561); Published functional studies demonstrated that p.(Y158D) generates a peak sodium current approximately two times larger than wild-type SCN10A channels, and when co-expressed with p.(R814H), the magnitude of the peak current was close to the sum of the average value of the peak currents of each variant expressed individually, such that both variants are reported to contribute to the electrical property of the channel; however, additional studies are needed to validate the functional effect of this variant in vivo (PMID: 25053638); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25053638, 26733327, 28407228, 29396561, 34426522, 37194601, 37175987, 25691686) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Episodic pain syndrome, familial, 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 13, 2018	The p.Tyr158Asp has been reported on the same chromosome together with p. Arg814His, constituting a complex variant p.[Tyr158Asp, Arg814His] in several adult individuals with atrial fibrillation/polarization abnormality (Savio-Galimberti 2014, Jabbari 2015, Te Riele 2016). The Tyr158Asp and Arg814His variants were also identified in the study of patients with AV nodal reentrant tachycardia (Andreasen 2018). Savio-Galimberti et al. (2014) reported two families with possible variable penetrance and also showed that that these variants were associated with 2- and 4-fold increase in peak currents in a transient transfection and expression experiments in ND7/23 cells. Both Tyr158Asp and Arg814His variants are listed in gnomAD at population frequencies 0.04 and 0.05%, higher than expected for a pathogenic variant (Kobayashi 2017). Both variants are listed in ClinVar with current classification of uncertain significance (Variant ID 463260 and 420025). Thus, based on the available evidence, the complex variant p.[Tyr158Asp, Arg814His] was classified as of uncertain significance. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 14, 2021

- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2020

This sequence change replaces tyrosine with aspartic acid at codon 158 of the SCN10A protein (p.Tyr158Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs202192818, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with atrial fibrillation and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 25053638, 25085921, 26733327). All reported individuals also carried another change (c.2441G>A, p.Arg814His) that was shown to be in cis in at least three individuals (PMID: 25053638, 26733327). ClinVar contains an entry for this variant (Variation ID: 463260). Experimental studies in vitro have shown that this missense change generates a peak current that is 2 times larger than that of wild type (PMID: 25053638). 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

Oct 31, 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

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;M;.

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-8.8

D;.;.;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Uncertain

0.029

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.82

MVP

0.98

MPC

0.44

ClinPred

0.96

GERP RS

2.7

Varity_R

0.79

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00050

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.34

Position offset: 1

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