chr3-38728741-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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. 13/21 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 0.00039 ( 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:8B:2

Conservation

PhyloP100: -1.70

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 Likely_benign. Variant got -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 id is 420025.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 60 AD 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

GnomAD3 exomes

AF:

0.000279

AC:

AN:

250764

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135608

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000582

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000394

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000241

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:

0.000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000526

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:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

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) -

Nov 24, 2019

Mayo Clinic Laboratories, Mayo Clinic

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. -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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;.

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

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

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