3-38726839-G-C

Position:

• chr3-38726839-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006514.4(SCN10A):​c.2854C>G​(p.Pro952Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.139

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24225083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2854C>G	p.Pro952Ala	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.2854C>G	p.Pro952Ala	missense_variant	17/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1	c.2881C>G	p.Pro961Ala	missense_variant	17/28			ENSP00000499510
SCN10A	ENST00000643924.1	c.2854C>G	p.Pro952Ala	missense_variant	16/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2018

This sequence change replaces proline with alanine at codon 952 of the SCN10A protein (p.Pro952Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN10A-related disease. 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"). The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.046	T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.62	.;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.73	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.99	N;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.35	T;.;.;.
Sift4G	Benign	0.56	T;.;.;.
Polyphen		0.015	B;.;B;.
Vest4		0.14
MutPred		0.73		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.74
MPC		0.065
ClinPred		0.12	T
GERP RS		4.4
Varity_R		0.089
gMVP		0.12

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: rs370880796; hg19: chr3-38768330;