rs1450059546

Positions:

• chr3-38722410-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006514.4(SCN10A):​c.3355T>A​(p.Cys1119Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.3355T>A	p.Cys1119Ser	missense_variant, splice_region_variant	20/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.3355T>A	p.Cys1119Ser	missense_variant, splice_region_variant	20/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.3379T>A	p.Cys1127Ser	missense_variant, splice_region_variant	20/28
SCN10A	ENST00000643924.1	c.3352T>A	p.Cys1118Ser	missense_variant, splice_region_variant	19/27			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461054 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Apr 03, 2017

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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces cysteine with serine at codon 1119 of the SCN10A protein (p.Cys1119Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-9.3	D;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0040	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.83
MutPred		0.83		Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);.;
MVP		0.83
MPC		0.40
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1450059546; hg19: chr3-38763901;