3-38728696-C-T

Position:

• chr3-38728696-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_006514.4(SCN10A):​c.2486G>A​(p.Arg829His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.86

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2486G>A	p.Arg829His	missense_variant	16/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2486G>A	p.Arg829His	missense_variant	16/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1	c.2513G>A	p.Arg838His	missense_variant	16/28			ENSP00000499510
SCN10A	ENST00000643924.1	c.2486G>A	p.Arg829His	missense_variant	15/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251294 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 09, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 829 of the SCN10A protein (p.Arg829His). This variant is present in population databases (rs752623537, gnomAD 0.003%). 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: 532093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN10A protein function. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.R829H variant (also known as c.2486G>A), located in coding exon 15 of the SCN10A gene, results from a G to A substitution at nucleotide position 2486. The arginine at codon 829 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.9	D;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.015	D;.;.;.
Sift4G	Uncertain	0.019	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.78
MutPred		0.68		Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);
MVP		0.92
MPC		0.24
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.88

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

Other links and lift over

dbSNP: rs752623537; hg19: chr3-38770187; COSMIC: COSV71860263;