chr3-38792120-T-A

Variant names:

• chr3-38792120-T-A
• rs757050845
• NM_006514.4:c.319A>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006514.4(SCN10A):​c.319A>T​(p.Thr107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.12

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.319A>T	p.Thr107Ser	missense_variant	Exon 3 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.319A>T	p.Thr107Ser	missense_variant	Exon 3 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.319A>T	p.Thr107Ser	missense_variant	Exon 2 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.319A>T	p.Thr107Ser	missense_variant	Exon 3 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251070 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Uncertain:1

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 107 of the SCN10A protein (p.Thr107Ser). This variant is present in population databases (rs757050845, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 576565). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN10A protein function. 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. -

Cardiovascular phenotype Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T107S variant (also known as c.319A>T), located in coding exon 2 of the SCN10A gene, results from an A to T substitution at nucleotide position 319. The threonine at codon 107 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	.;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.0	M;.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;.;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.040	D;.;.;.
Sift4G	Benign	0.15	T;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.33
MutPred		0.38		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.95
MPC		0.062
ClinPred		0.77	D
GERP RS		4.0
Varity_R		0.35
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs757050845; hg19: chr3-38833611; COSMIC: COSV105360642;