rs138832868

Variant names:

• chr3-38713959-C-T
• rs138832868
• NM_006514.4:c.3803G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006514.4(SCN10A):​c.3803G>A​(p.Arg1268Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,613,264 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (11 hom.)
• Consequence: SCN10A NM_006514.4 missense, splice_region
• Scores: Splicing: ADA: 0.7424
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030475438).
• BP6: Variant 3-38713959-C-T is Benign according to our data. Variant chr3-38713959-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240673.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}. Variant chr3-38713959-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 370 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.3803G>A	p.Arg1268Gln	missense_variant, splice_region_variant	Exon 22 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.3803G>A	p.Arg1268Gln	missense_variant, splice_region_variant	Exon 22 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.3800G>A	p.Arg1267Gln	missense_variant, splice_region_variant	Exon 21 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.3827G>A	p.Arg1276Gln	missense_variant, splice_region_variant	Exon 22 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00166 AC: 416 AN: 251046 Hom.: 2 AF XY: 0.00173 AC XY: 234 AN XY: 135650

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00288

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00252 AC: 3678 AN: 1460986 Hom.: 11 Cov.: 30 AF XY: 0.00242 AC XY: 1757 AN XY: 726776

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00244

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00175 AC: 213

EpiCase AF: 0.00240

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Aug 14, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the SCN10A gene. The R1268Q variant has previously been reported in association with Brugada syndrome and atrial fibrillation (Hu et al., 2014; Behr et al., 2015; Jabbari et al., 2015). In addition, Choi et al. (2010) identified this variant in a Dutch man with erythromelalgia who also harbored a missense variant in SCN9A. The R1268Q variant was not identified in any relatives, while the SCN9A variant was observed in two affected sons and an unaffected daughter of the proband (Choi et al., 2010). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, occurring at a position that is conserved across species. Functional studies by Hu et al. (2014) demonstrate that R1268Q results in significantly reduced channel current density compared to wild-type. However, the Exome Aggregation Consortium (ExAC) reports R1268Q was observed in 29/6,592 (0.4%) alleles from individuals of European (Finnish) ancestry and 167/66,390 (0.2%) alleles from individuals of European (Non-Finnish) ancestry, indicating it may be a rare benign variant in these populations (Lek et al., 2016). Furthermore, this variant lacks segregation data which could further clarify its pathogenicity. -

Oct 23, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN10A: BS1, BS2 -

Dec 11, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Arg1268Gln (c.3803G>A) in exon 21 of the SCN10A gene (NM_006514.2; 3: 38755450 20, rs138832868) SCICD Classification: likely benign based on lack of evidence associating SCN10A with disease and the high frequency of this variant in the general population. It may be a modifier of disease but due to the high frequency in the general population, it is unlikely to be disease-causing on its own. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Testing was done at GeneDx. Gene-level evidence: SCN10A encodes the alpha subunit of a voltage-gated sodium channel. Pathogenic variants in SCN10A have been associated with familial episodic pain syndrome. There is weak data that it could also contribute to cardiac conduction diseases. It has been proposed that some variants in SCN10A modulate expression of SCN5A in patients with Brugada syndrome (Bezzinea et al 2013, Chambers et al 2010, van den Boogaard et al 2014). SCN10A remains a gene of uncertain significance. Case data (not including our patient): ClinVar: Invitae classifies this variant as benign Cases in the literature: Choi et al 2010: this variant was identified in a Dutch man with erythromelalgia who also had a missense variant in SCN9A. The R1268Q variant was not observed in the patient, but not in his two affected sons. Hu et al 2014: R1268Q reportedly significantly reduces ion channel current density compared to wild-type Behr et al 2015: Jabbari et al 2015: Abou Ziki et al 2017: Segregation data: this variant did not segregate with erythromelalgia in a Dutch patient. Functional data: Hu et al: R1268Q significantly reduces channel current density compared to wild-type. In silico data (missense variants only): Per the test report, "This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, occurring at a position that is conserved across species." Conservation data: The arginine at codon 1268 is completely conserved across species. Neighboring amino acids are completely or almost completely conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in European population: 0.3%. The variant was reported online in 2 homozygotes and in 520 heterozygotes in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 400 of 63,263 individuals of European descent (MAF=0.3%), but is found at appreciable frequency in all other populations. 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. -

Brugada syndrome 1 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic pain syndrome, familial, 2 Uncertain:1

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 22, 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	0.33
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;D;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Uncertain	0.0070	D;.;.;.
Polyphen		0.086	B;.;B;.
Vest4		0.92
MVP		0.92
MPC		0.11
ClinPred		0.062	T
GERP RS		4.1
Varity_R		0.72
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.63
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

Other links and lift over

dbSNP: rs138832868; hg19: chr3-38755450; COSMIC: COSV99081711;