rs1553619005

Variant names:

• chr3-38742345-C-T
• rs1553619005
• NM_006514.4:c.2052G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006514.4(SCN10A):​c.2052G>A​(p.Met684Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. M684V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 1 publications found

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]

SCN10A Gene-Disease associations (from GenCC):

• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2052G>A	p.Met684Ile	missense_variant	Exon 14 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2052G>A	p.Met684Ile	missense_variant	Exon 14 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.2052G>A	p.Met684Ile	missense_variant	Exon 13 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.2079G>A	p.Met693Ile	missense_variant	Exon 14 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Jul 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change replaces methionine with isoleucine at codon 684 of the SCN10A protein (p.Met684Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	2.9	M;.;M;.
PhyloP100		4.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Benign	0.087	T;.;.;.
Polyphen		0.58	P;.;P;.
Vest4		0.60
MutPred		0.48		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.81
MPC		0.075
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.54
gMVP		0.49
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs1553619005; hg19: chr3-38783836; COSMIC: COSV71862637;