rs1553626242

Positions:

• chr3-38793891-C-A

Variant summary

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

The ENST00000449082.3(SCN10A):​c.120G>T​(p.Lys40Asn) 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: 32)
• Consequence: SCN10A ENST00000449082.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.664

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=0.17177036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.120G>T	p.Lys40Asn	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.120G>T	p.Lys40Asn	missense_variant	2/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1	c.120G>T	p.Lys40Asn	missense_variant	2/28			ENSP00000499510
SCN10A	ENST00000643924.1	c.120G>T	p.Lys40Asn	missense_variant	1/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jun 16, 2017

In summary, this variant has uncertain impact on SCN10A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a SCN10A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 40 of the SCN10A protein (p.Lys40Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;.;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.65	.;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	1.5	L;.;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.86	N;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.041	D;.;.;.
Sift4G	Benign	0.14	T;.;.;.
Polyphen		0.84	P;.;P;.
Vest4		0.29
MutPred		0.24		Gain of ubiquitination at K45 (P = 0.0231);Gain of ubiquitination at K45 (P = 0.0231);Gain of ubiquitination at K45 (P = 0.0231);Gain of ubiquitination at K45 (P = 0.0231);
MVP		0.73
MPC		0.11
ClinPred		0.24	T
GERP RS		3.2
Varity_R		0.081
gMVP		0.40

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: rs1553626242; hg19: chr3-38835382;