rs7617919

chr3-38752498-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006514.4(SCN10A):c.1476C>T(p.Leu492=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,588,222 control chromosomes in the GnomAD database, including 47,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3705 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43642 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.20

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-38752498-G-A is Benign according to our data. Variant chr3-38752498-G-A is described in ClinVar as [Benign]. Clinvar id is 259992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38752498-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• 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.1476C>T	p.Leu492=	synonymous_variant	12/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.1476C>T	p.Leu492=	synonymous_variant	12/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.1503C>T	p.Leu501=	synonymous_variant	12/28
SCN10A	ENST00000643924.1	c.1476C>T	p.Leu492=	synonymous_variant	11/27			A1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31307 AN: 152038 Hom.: 3705 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.233 AC: 53412 AN: 229124 Hom.: 6923 AF XY: 0.239 AC XY: 29589 AN XY: 123944

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.389

Gnomad SAS exome AF: 0.231

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.241 AC: 346768 AN: 1436066 Hom.: 43642 Cov.: 33 AF XY: 0.242 AC XY: 172275 AN XY: 711868

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.206 AC: 31310 AN: 152156 Hom.: 3705 Cov.: 32 AF XY: 0.207 AC XY: 15411 AN XY: 74368

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.200

Alfa AF: 0.233 Hom.: 5241

Bravo AF: 0.193

Asia WGS AF: 0.270 AC: 940 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 18, 2017	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Episodic pain syndrome, familial, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.3
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7617919; hg19: chr3-38793989; COSMIC: COSV71860666;