chr3-38726877-G-A

Position:

chr3-38726877-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006514.4(SCN10A):c.2816C>T(p.Pro939Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,614,096 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.464

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026501745).

BP6

Variant 3-38726877-G-A is Benign according to our data. Variant chr3-38726877-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407747.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.2816C>T	p.Pro939Leu	missense_variant	17/28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 link	c.2816C>T	p.Pro939Leu	missense_variant	17/28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 link	c.2816C>T	p.Pro939Leu	missense_variant	16/27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 link	c.2843C>T	p.Pro948Leu	missense_variant	17/28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251328

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000186

AC:

272

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000138

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 09, 2017	p.Pro939Leu (P939L; c.2816C>T) in exon 16 of the SCN10A gene (NM_006514.3) Chromosome position 3:38768368 G / A We classify this as a variant of uncertain significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. It has not been reported in another person with our patientâ€™s phenotype as of 4/12/2017, it is in a gene of uncertain significance, and it is found in the general population at an appreciable frequency. This variant has been reported in one individual affected with painful peripheral neuropathy (Faber et al. 2012, PMID: 23115331). However, it did not meet the authorsâ€™ criteria to move on to functional in vitro studies (criteria: <1% allelic frequency in public databases, segregation in affected individuals when available to test, alteration of a conserved residue in a transmembrane segment or a previously identified functional motif that regulates channel current). This is a conservative amino acid change, resulting in the replacement of a nonpolar Proline with a nonpolar Leucine. Proline at this location is poorly conserved across vertebrate species, and is frequently replaced by Alanine, Serine, or Arginine. Leucine is the default amino acid in at least one mammalian species. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side as of 4/11/2017. 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 tolerated, but these predictions have not been confirmed by published functional studies. In total the variant has been seen in at least 69 out of >140,000 individuals from publicly available population datasets. Specifically, it was reported in 16/5,069 Ashkenazi Jewish, 12/9,434 East Asian, 8/15,391 South Asian, 27/63,271 non-Finnish European, 4/17,209 Latino, and 2/3,232 â€œOtherâ€ ancestry individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Out patientâ€™s ancestry is Latino. The overall allele frequency in gnomAD is 0.02%, and the highest allele frequency is 0.16% in Ashkenazi Jews. This would translate into 1 in 317 people with Ashkenazi Jewish ancestry having the variant (which is likely too common to be a cause of Brugada syndrome). 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	Jan 03, 2019	The P939L variant in the SCN10A gene has been reported previously as heterozygous in an individual with painful neuropathy, however it is unclear if this patient was compound heterozygous for another variant (Faber et al., 2012). The P939L variant is observed in 69/277034 (0.025%) alleles in large population cohorts (Lek et al., 2016). The P939L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret P939L as a variant of uncertain significance. -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2020

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

Benign

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.062

T;.;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.40

.;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.035

N;.;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.83

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.043

D;.;.;.

Sift4G

Benign

0.24

T;.;.;.

Polyphen

0.24

B;.;B;.

Vest4

0.12

MVP

0.65

MPC

0.062

ClinPred

0.013

GERP RS

3.4

Varity_R

0.032

gMVP

0.16

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

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