rs750771811

Positions:

• chr3-38793971-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006514.4(SCN10A):​c.40C>T​(p.Arg14Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R14L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.81

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.40C>T	p.Arg14Cys	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.40C>T	p.Arg14Cys	missense_variant	2/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1	c.40C>T	p.Arg14Cys	missense_variant	2/28			ENSP00000499510
SCN10A	ENST00000643924.1	c.40C>T	p.Arg14Cys	missense_variant	1/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250812 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135512

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727128

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 569822). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. This variant is present in population databases (rs750771811, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 14 of the SCN10A protein (p.Arg14Cys). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.40C>T (p.R14C) alteration is located in exon 1 (coding exon 1) of the SCN10A gene. This alteration results from a C to T substitution at nucleotide position 40, causing the arginine (R) at amino acid position 14 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.6	D;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.0060	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.60
MutPred		0.67		Gain of glycosylation at T17 (P = 0.0067);Gain of glycosylation at T17 (P = 0.0067);Gain of glycosylation at T17 (P = 0.0067);Gain of glycosylation at T17 (P = 0.0067);
MVP		0.94
MPC		0.38
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.40
gMVP		0.62

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: rs750771811; hg19: chr3-38835462;