rs778131235

chr3-38728897-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_006514.4(SCN10A):c.2285G>A(p.Arg762His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,604,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R762S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.2285G>A	p.Arg762His	missense_variant	16/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.2285G>A	p.Arg762His	missense_variant	16/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.2312G>A	p.Arg771His	missense_variant	16/28
SCN10A	ENST00000643924.1	c.2285G>A	p.Arg762His	missense_variant	15/27			A1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245798 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 132904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1452794 Hom.: 0 Cov.: 31 AF XY: 0.0000180 AC XY: 13 AN XY: 721040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000677

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000905

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74246

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 24, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 579887). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. This variant is present in population databases (rs778131235, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 762 of the SCN10A protein (p.Arg762His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	H;.;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D;.;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.010	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.81
MVP		0.98
MPC		0.42
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.96

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: rs778131235; hg19: chr3-38770388; COSMIC: COSV71861217;