3-38698510-C-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.4710G>A(p.Thr1570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,613,984 control chromosomes in the GnomAD database, including 1,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (150 hom., cov: 31)
  • Exomes 𝑓: 0.022 (1241 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.56

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=-0.79).
• BP6: Variant 3-38698510-C-T is Benign according to our data. Variant chr3-38698510-C-T is described in ClinVar as [Benign]. Clinvar id is 95403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698510-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.4710G>A	p.Thr1570=	synonymous_variant	28/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.4710G>A	p.Thr1570=	synonymous_variant	28/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.4734G>A	p.Thr1578=	synonymous_variant	28/28
SCN10A	ENST00000643924.1	c.4707G>A	p.Thr1569=	synonymous_variant	27/27			A1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3489 AN: 152054 Hom.: 150 Cov.: 31

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0393 AC: 9862 AN: 250920 Hom.: 553 AF XY: 0.0370 AC XY: 5012 AN XY: 135580

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0860

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.208

Gnomad SAS exome AF: 0.0296

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0219 AC: 31983 AN: 1461812 Hom.: 1241 Cov.: 35 AF XY: 0.0220 AC XY: 15974 AN XY: 727190

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0857

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.0317

Gnomad4 FIN exome AF: 0.00586

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0230 AC: 3496 AN: 152172 Hom.: 150 Cov.: 31 AF XY: 0.0254 AC XY: 1889 AN XY: 74406

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.0665

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.0331

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0147 Hom.: 13

Bravo AF: 0.0276

Asia WGS AF: 0.0830 AC: 287 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 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	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 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. -

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 27, 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	-0.79
Cadd	Benign	0.15
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs78425180; hg19: chr3-38740001; COSMIC: COSV71862630;