rs6771157

chr3-38722372-G-Cchr3-38722372-G-T

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.3393C>G(p.Thr1131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,744 control chromosomes in the GnomAD database, including 51,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1131T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4092 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47339 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.553

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=-0.87).
• BP6: Variant 3-38722372-G-C is Benign according to our data. Variant chr3-38722372-G-C is described in ClinVar as [Benign]. Clinvar id is 259998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38722372-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.553 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.3393C>G	p.Thr1131=	synonymous_variant	20/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.3393C>G	p.Thr1131=	synonymous_variant	20/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.3417C>G	p.Thr1139=	synonymous_variant	20/28
SCN10A	ENST00000643924.1	c.3390C>G	p.Thr1130=	synonymous_variant	19/27			A1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33546 AN: 151952 Hom.: 4092 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.239 AC: 60154 AN: 251362 Hom.: 7888 AF XY: 0.244 AC XY: 33159 AN XY: 135846

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.388

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.250 AC: 365387 AN: 1461674 Hom.: 47339 Cov.: 35 AF XY: 0.250 AC XY: 181821 AN XY: 727164

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.332

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.221 AC: 33555 AN: 152070 Hom.: 4092 Cov.: 32 AF XY: 0.223 AC XY: 16542 AN XY: 74318

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.214

Alfa AF: 0.255 Hom.: 1746

Bravo AF: 0.208

Asia WGS AF: 0.272 AC: 947 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.248

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 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
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 22, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.57
Dann	Benign	0.28

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: rs6771157; hg19: chr3-38763863; COSMIC: COSV71860318;