chr3-38771406-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. Y158Y) has been classified as Likely benign.

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 P:1U:9B:1

Conservation

PhyloP100: 5.23

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
episodic pain syndrome, familial, 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

BS2

High AC in GnomAd4 at 46 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	Exon 5 of 28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 link	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	Exon 5 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	Exon 4 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	Exon 5 of 28			ENSP00000499510.1	A0A590UJM0

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

GnomAD2 exomes

AF:

0.000231

AC:

AN:

251360

AF XY:

0.000162

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 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

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.000201

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000496

AC:

551

AN:

1111754

Other (OTH)

AF:

0.000265

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41462

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68036

Other (OTH)

AF:

0.00191

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000435

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: Pathogenic:1Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Nov 24, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic pain syndrome, familial, 2

Uncertain:3

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome 1

Pathogenic:1Uncertain:1

Nov 20, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PS3, PP3, PP5; Variant was found in heterozygous state -

Oct 14, 2021

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SCN10A c.472T>G (p.Tyr158Asp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. In addition, the variant affects the second nucleotide of exon 5, therefore might also impact splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant no significant impact on splicing. One predict the variant weakens a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0004 in 1606700 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum for a pathogenic variant in SCN10A, allowing no conclusion about variant significance. Of note, this variant is typically reported in the literature as a complex (i.e. on the same allele) as c.2441G>A (p.Arg814His), and variant co-occurrence analysis in gnomAD indicates that these two missense variants are on the same haplotype in most individuals. The two missense variants c.472T>G (p.Tyr158Asp) and c.2441G>A (p.Arg814His) has been observed together in individuals affected with SCN10A-Related Disorders, including arrhythmia and neuropathy, however no segregation evidence was provided to support causality (e.g. Savio-Galimberti_2014, Jabbari_2015, TeRiele_2016, Almomani_2023). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that both missense variants in isolation and together as a complex, affected sodium channel function, resulting in increased currents, and the two missense seemed to result in an additive effect when expressed together (Savio-Galimberti_2014), however, these results do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 25053638, 25691686, 26733327, 37175987). ClinVar contains an entry for this variant (Variation ID: 463260). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 158 of the SCN10A protein (p.Tyr158Asp). This variant is present in population databases (rs202192818, gnomAD 0.04%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy and/or atrial fibrillation (PMID: 25053638, 25691686, 26733327). ClinVar contains an entry for this variant (Variation ID: 463260). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN10A function (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

Oct 31, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

5.2

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

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over