chr3-38726877-G-A

Variant names:

• chr3-38726877-G-A
• rs202174472
• NM_006514.4:c.2816C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P939P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.464
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 407747.
• BS2: High AC in GnomAd4 at 21 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2816C>T	p.Pro939Leu	missense_variant	Exon 17 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2816C>T	p.Pro939Leu	missense_variant	Exon 17 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.2816C>T	p.Pro939Leu	missense_variant	Exon 16 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.2843C>T	p.Pro948Leu	missense_variant	Exon 17 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152206 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.000267 AC: 67 AN: 251328 AF XY: 0.000287

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 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.: 1 Cov.: 33 AF XY: 0.000227 AC XY: 165 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1112008

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152206 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000384 AC: 2 AN: 5204

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00949 AC: 3 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.0000925 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jan 03, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 09, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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 patient’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 authors’ 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 “Other” 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 patient’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. -

Brugada syndrome Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 02, 2020

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	Benign	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.65
DEOGEN2	Benign	0.062	T;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.40	.;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.035	N;.;N;.
PhyloP100		0.46
PrimateAI	Benign	0.26	T
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	T
GERP RS		3.4
Varity_R		0.032
gMVP		0.16
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs202174472; hg19: chr3-38768368; COSMIC: COSV104716768;