chr3-38726851-C-T

Position:

• chr3-38726851-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006514.4(SCN10A):​c.2842G>A​(p.Val948Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. V948L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.346

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1783796).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2842G>A	p.Val948Met	missense_variant	17/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2842G>A	p.Val948Met	missense_variant	17/28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.2842G>A	p.Val948Met	missense_variant	16/27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.2869G>A	p.Val957Met	missense_variant	17/28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461758 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727160

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 23, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 948 of the SCN10A protein (p.Val948Met). This variant is not present in population databases (gnomAD no frequency). 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: 532079). 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 not 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

Aug 26, 2024

The c.2842G>A (p.V948M) alteration is located in exon 16 (coding exon 16) of the SCN10A gene. This alteration results from a G to A substitution at nucleotide position 2842, causing the valine (V) at amino acid position 948 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.048	T;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	.;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N;.;N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.58	N;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.13	T;.;.;.
Sift4G	Benign	0.14	T;.;.;.
Polyphen		0.055	B;.;B;.
Vest4		0.057
MutPred		0.67		Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);
MVP		0.62
MPC		0.076
ClinPred		0.068	T
GERP RS		2.5
Varity_R		0.047
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145694222; hg19: chr3-38768342;