rs145712124

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 5.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=2, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.2428G>T	p.Gly810Trp	missense_variant	16/28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 linkuse as main transcript	c.2428G>T	p.Gly810Trp	missense_variant	16/28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 linkuse as main transcript	c.2428G>T	p.Gly810Trp	missense_variant	15/27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 linkuse as main transcript	c.2455G>T	p.Gly819Trp	missense_variant	16/28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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:

AN:

250354

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135402

show subpopulations

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.:

Cov.:

AF XY:

0.000579

AC XY:

421

AN XY:

727248

show subpopulations

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:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74460

show subpopulations

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.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 24, 2018	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.) Invitaeâ€™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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2023	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SCN10A: BS2 -

Episodic pain syndrome, familial, 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 30, 2021	- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

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 (PMID: 25053638). ClinVar contains an entry for this variant (Variation ID: 463239). 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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2019

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

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

.;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;H;.

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over