3-38728754-C-A

Variant names:

• chr3-38728754-C-A
• rs145712124
• NM_006514.4:c.2428G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_006514.4(SCN10A):​c.2428G>T​(p.Gly810Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000575 in 1,614,186 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 5.01

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, 0.891
• BP6: Variant 3-38728754-C-A is Benign according to our data. Variant chr3-38728754-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463239.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2428G>T	p.Gly810Trp	missense_variant	Exon 16 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2428G>T	p.Gly810Trp	missense_variant	Exon 16 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.2428G>T	p.Gly810Trp	missense_variant	Exon 15 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.2455G>T	p.Gly819Trp	missense_variant	Exon 16 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 71 AN: 250354 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135402

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000492

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: 0.000462

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000605 AC: 885 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000579 AC XY: 421 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000402

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: 0.000742

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74460

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Nov 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with paroxysmal atrial fibrillation and small fiber neuropathy (PMID: 25053638, 36895957); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36895957, 25053638) -

Jan 24, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Gly810Trp (G810W; c.2428G>T) in exon 15 of the SCN10A gene (NM_006514.3) Chromosome location 3:38770245 C / A Found in a 12-year-old male with a history of 2 unexplained syncopal episodes and a run of monomorphic VT on Holter monitor. Based on the information reviewed below, including a lack of case data, and prevalence in the broader population, we classify this as a VUS, Probably Benign. This variant is most common among individuals with Latino ancestry like our patient, and it may therefore be a benign ethnicity-specific variant. This variant has previously been reported in a European-American male individual diagnosed at age 51 with paroxysmal atrial fibrillation (PMID: 25053638). There is no published segregation data. This is a conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a nonpolar Tryptophan that has a much larger side chain. Glycine at this location is highly conserved across ~100 vertebrate species for which we have data, although it is a Serine in two mammalian species and an Arginine in another. The adjacent residues are not highly conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 75 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 17 Latino individuals (for the highest allele frequency: 0.05%), 56 non-Finnish Europeans (MAF 0.04%), and 2 individuals with African ancestry. (There are also 2 individuals with p.Gly810Arg.) Invitae’s report notes that it has an allele count higher than expected for a pathogenic variant. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN10A: BS2 -

Episodic pain syndrome, familial, 2 Uncertain:2

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2021

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 810 of the SCN10A protein (p.Gly810Trp). This variant is present in population databases (rs145712124, gnomAD 0.05%). This missense change has been observed in individual(s) with atrial fibrillation or small fiber neuropathy and/or epilepsy (PMID: 25053638, 36895957, 37993639). ClinVar contains an entry for this variant (Variation ID: 463239). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN10A protein function with a positive predictive value of 80%. 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. -

not specified Benign:1

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN10A c.2428G>T (p.Gly810Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250354 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 78 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN10A causing Arrhythmia phenotype (6.3e-06). To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 463239). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Dec 10, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.8	D;.;.;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0070	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.69
MVP		0.94
MPC		0.40
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.77
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145712124; hg19: chr3-38770245;