rs12632942

Positions:

• chr3-38723507-A-G
• chr3-38723507-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006514.4(SCN10A):​c.3275T>C​(p.Leu1092Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,611,844 control chromosomes in the GnomAD database, including 51,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4103 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47227 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.776

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020908415).
• BP6: Variant 3-38723507-A-G is Benign according to our data. Variant chr3-38723507-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38723507-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.3275T>C	p.Leu1092Pro	missense_variant	19/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.3275T>C	p.Leu1092Pro	missense_variant	19/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.3299T>C	p.Leu1100Pro	missense_variant	19/28
SCN10A	ENST00000643924.1	c.3272T>C	p.Leu1091Pro	missense_variant	18/27			A1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33587 AN: 152066 Hom.: 4103 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.240 AC: 58530 AN: 243924 Hom.: 7572 AF XY: 0.245 AC XY: 32303 AN XY: 132000

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.389

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.250 AC: 364980 AN: 1459660 Hom.: 47227 Cov.: 34 AF XY: 0.250 AC XY: 181556 AN XY: 725990

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.332

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.221 AC: 33596 AN: 152184 Hom.: 4103 Cov.: 33 AF XY: 0.223 AC XY: 16583 AN XY: 74406

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.214

Alfa AF: 0.246 Hom.: 12059

Bravo AF: 0.209

TwinsUK AF: 0.250 AC: 926

ALSPAC AF: 0.241 AC: 928

ESP6500AA AF: 0.142 AC: 625

ESP6500EA AF: 0.260 AC: 2236

ExAC AF: 0.241 AC: 29298

Asia WGS AF: 0.272 AC: 946 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Episodic pain syndrome, familial, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

This alteration is classified as 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	0.046
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.84
DEOGEN2	Benign	0.036	T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0069	N
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N;.;N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.2	N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.60	T;.;.;.
Sift4G	Benign	0.41	T;.;.;.
Polyphen		0.0	B;.;B;.
Vest4		0.013
MPC		0.092
ClinPred		0.0018	T
GERP RS		-0.53
Varity_R		0.087
gMVP		0.40

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: rs12632942; hg19: chr3-38764998; COSMIC: COSV71861243;