3-38728741-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_006514.4(SCN10A):c.2441G>A(p.Arg814His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,614,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R814C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: -1.70

Publications

12 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38756487).

BP6

Variant 3-38728741-C-T is Benign according to our data. Variant chr3-38728741-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420025.

BS2

High AC in GnomAd4 at 60 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.2441G>A	p.Arg814His	missense_variant	Exon 16 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.2441G>A	p.Arg814His	missense_variant	Exon 16 of 28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.2441G>A	p.Arg814His	missense_variant	Exon 15 of 27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.2468G>A	p.Arg823His	missense_variant	Exon 16 of 28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.000588

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000279

AC:

AN:

250764

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.000460

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000486

AC:

711

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000582

AC:

647

AN:

1112006

Other (OTH)

AF:

0.000364

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000394

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.000327

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000507

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Arg814His (c.2441G>A) in exon 15 of the SCN10A gene (NM_006514.3) Chromosome position: 3:38770232 C / T Found in a male patient with early-onset lone atrial fibrillation. The SCN10A gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with Brugada syndrome (BrS) (PMID: 24998131). Based on the information reviewed below, including this variantâ€™s prevalence in population databases, and how poorly conserved this residue is across evolution, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has been reported in 4 probands: 3 affected with early-onset atrial fibrillation (2 from Savio-Galimberti et al., 2014, PMID: 25053638; and 1 from Jabbari et al., 2015, PMID: 25691686) and 1 with arrhythmogenic right ventricular dysplasia/cardiomyopathy (Te Riele et al., 2016, PMID: 26733327). All reported individuals also carried another change (c.472T>G, p.Tyr158Asp) that was shown to be on the same allele (in cis) in at least three of these cases (Savio-Galimberti et al., 2014, PMID: 25053638; Te Riele et al., 2016, PMID 26733327). Savio-Galimberti et al. (2014) report that in their two families, first degree relatives with the variant(s) did not show atrial fibrillation, possibly due to reduced penetrance. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is very poorly conserved across ~100 vertebrate species for which we have data. There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10). Experimental studies in vitro have shown that this missense change generates a peak current that is 4 times larger than that of wild type (Savio-Galimberti et al., 2014; PMID: 25053638). This variant was reported in 85 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. (MAF = 0.03%.) Specifically, the variant was observed in 63 individuals with non-Finnish European ancestry (for the highest allele frequency: 0.05%), and 7 individuals with Latino ancestry, 5 African ancestry, 4 Finnish ancestry, 3 South Asian ancestry, and 3 â€œOtherâ€. Our patientâ€™s ancestry is Latino. This variant is present at a higher frequency than would be expected for a pathogenic variant. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

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, or diabetic peripheral neuropathy, many of whom also harbored the p.(Y158D) variant in the SCN10A gene in either cis or unknown configuration (PMID: 25053638, 25691686, 26733327, 28407228, 29396561, 31638414); Published functional studies demonstrated that p.(R814H) generates a peak sodium current approximately four times larger than wild-type SCN10A channels, and when co-expressed with p.(Y158D), 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 indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28407228, 25691686, 26733327, 31638414, 29396561, 34426522, 37175987, 25053638) -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 24, 2019

Mayo Clinic Laboratories, Mayo Clinic

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.2441G>A (p.Arg814His) 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 are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00048 in 1607170 control chromosomes, predominantly at a frequency of 0.00058 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) with c.472T>G (p.Tyr158Asp), 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: 420025). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1

Uncertain:1

Oct 14, 2021

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic pain syndrome, familial, 2

Uncertain:1

Aug 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.083

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.41

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.;D;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.39

.;T;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.2

L;.;L;.

PhyloP100

-1.7

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.9

N;.;.;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0080

D;.;.;.

Sift4G

Benign

0.076

T;.;.;.

Polyphen

0.93

P;.;P;.

Vest4

0.75

MVP

0.61

MPC

0.074

ClinPred

0.032

GERP RS

-1.3

Varity_R

0.064

gMVP

0.39

Mutation Taster

=39/61

disease causing

(source)

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

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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