rs201106879

Variant names:

• chr3-38726623-C-T
• rs201106879
• NM_006514.4:c.3070G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006514.4(SCN10A):​c.3070G>A​(p.Val1024Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,590,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.333
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028200984).
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.3070G>A	p.Val1024Met	missense_variant	Exon 17 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.3070G>A	p.Val1024Met	missense_variant	Exon 17 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.3070G>A	p.Val1024Met	missense_variant	Exon 16 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.3097G>A	p.Val1033Met	missense_variant	Exon 17 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 243042 AF XY: 0.0000230

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437718 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 710344

African (AFR) AF: 0.0000905 AC: 3 AN: 33152

American (AMR) AF: 0.0000453 AC: 2 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.00 AC: 0 AN: 83456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094792

Other (OTH) AF: 0.00 AC: 0 AN: 59264

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74496

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 25, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Val1024Met (c.3070G>A) in exon 16 of the SCN10A gene (NM_006514.3) Chromosome position: 3:38768114 C / T The SCN10A gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant small fiber neuropathy (SFNP) (PMID: 23986244) and Brugada syndrome (BrS) (PMID: 24998131). Based on the information reviewed below, including that this is a conservative amino acid change at a residue that is poorly conserved across species, and where Methionine is accepted as the default in some species, 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 not previously been reported in the literature in association with disease. It had not been reported to ClinVar as of 4/25/2017. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is poorly conserved across ~80 vertebrate species for which we have data. In fact, Methionine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". These predictions have not been confirmed by published functional studies. There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10). This variant was reported in 4 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 individuals with African ancestry (for the highest allele frequency: 0.013%), and 2 individuals with Latino ancestry. Our patient’s ancestry is Latino. 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. -

Feb 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with early onset atrial fibrillation and a structurally normal heart who also harbored a truncating variant in the TTN gene (PMID: 31638414); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24998131, 23986244, 31638414) -

Brugada syndrome Uncertain:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1024 of the SCN10A protein (p.Val1024Met). This variant is present in population databases (rs201106879, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463246). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN10A protein function with a negative predictive value of 95%. 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 Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1024M variant (also known as c.3070G>A), located in coding exon 16 of the SCN10A gene, results from a G to A substitution at nucleotide position 3070. The valine at codon 1024 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T;.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.58	.;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.028	T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.81	L;.;L;.
PhyloP100		-0.33
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.12	T;.;.;.
Sift4G	Benign	0.10	T;.;.;.
Polyphen		0.012	B;.;B;.
Vest4		0.094
MutPred		0.27		Loss of glycosylation at K1027 (P = 0.0202);Loss of glycosylation at K1027 (P = 0.0202);Loss of glycosylation at K1027 (P = 0.0202);Loss of glycosylation at K1027 (P = 0.0202);
MVP		0.53
MPC		0.064
ClinPred		0.037	T
GERP RS		1.8
Varity_R		0.043
gMVP		0.17
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201106879; hg19: chr3-38768114;