rs1226072923

Positions:

• chr3-38793748-G-A
• chr3-38793748-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006514.4(SCN10A):​c.263C>T​(p.Thr88Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.65

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34404707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.263C>T	p.Thr88Ile	missense_variant	2/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.263C>T	p.Thr88Ile	missense_variant	2/28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.263C>T	p.Thr88Ile	missense_variant	1/27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.263C>T	p.Thr88Ile	missense_variant	2/28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 26, 2017

This sequence change replaces threonine with isoleucine at codon 88 of the SCN10A protein (p.Thr88Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN10A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D;.
Eigen	Benign	0.019
Eigen_PC	Benign	-0.0021
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.0	M;.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.0040	D;.;.;.
Polyphen		0.72	P;.;P;.
Vest4		0.40
MutPred		0.45		Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);
MVP		0.87
MPC		0.15
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.20
gMVP		0.42

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: rs1226072923; hg19: chr3-38835239;