rs151182542

chr3-38701840-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006514.4(SCN10A):c.4656G>A(p.Ala1552=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,597,466 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: SCN10A NM_006514.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003792
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.40

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-38701840-C-T is Benign according to our data. Variant chr3-38701840-C-T is described in ClinVar as [Benign]. Clinvar id is 506666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38701840-C-T is described in Lovd as [Benign]. Variant chr3-38701840-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BS2: High AC in GnomAd at 619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.4656G>A	p.Ala1552=	splice_region_variant, synonymous_variant	27/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.4656G>A	p.Ala1552=	splice_region_variant, synonymous_variant	27/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.4680G>A	p.Ala1560=	splice_region_variant, synonymous_variant	27/28
SCN10A	ENST00000643924.1	c.4653G>A	p.Ala1551=	splice_region_variant, synonymous_variant	26/27			A1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00118 AC: 284 AN: 239864 Hom.: 4 AF XY: 0.000990 AC XY: 128 AN XY: 129244

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000362

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000862

GnomAD4 exome AF: 0.000537 AC: 776 AN: 1445112 Hom.: 6 Cov.: 31 AF XY: 0.000508 AC XY: 364 AN XY: 716526

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.000948

Gnomad4 ASJ exome AF: 0.000626

Gnomad4 EAS exome AF: 0.0000513

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00416 AC XY: 310 AN XY: 74504

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.000996 Hom.: 1

Bravo AF: 0.00479

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2017	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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	SCN10A: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 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	1.8
Dann	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.098
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: rs151182542; hg19: chr3-38743331; COSMIC: COSV101479212;