rs6599250

Positions:

• chr3-38742538-T-C

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.1868-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,609,664 control chromosomes in the GnomAD database, including 316,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38358 hom., cov: 32)
  • Exomes 𝑓: 0.61 (277776 hom.)
• Consequence: SCN10A NM_006514.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006857
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.669

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 (BayesDel_noAF=-0.79).
• BP6: Variant 3-38742538-T-C is Benign according to our data. Variant chr3-38742538-T-C is described in ClinVar as [Benign]. Clinvar id is 259993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38742538-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.1868-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.1868-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006514.4	P4
SCN10A	ENST00000643924.1	c.1868-9A>G		splice_polypyrimidine_tract_variant, intron_variant				A1
SCN10A	ENST00000655275.1	c.1895-9A>G		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105735 AN: 151962 Hom.: 38285 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.649 AC: 161550 AN: 248812 Hom.: 53874 AF XY: 0.641 AC XY: 86427 AN XY: 134896

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.860

Gnomad SAS exome AF: 0.638

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.615

GnomAD4 exome AF: 0.614 AC: 894283 AN: 1457584 Hom.: 277776 Cov.: 32 AF XY: 0.613 AC XY: 444436 AN XY: 725452

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.858

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.542

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.630

GnomAD4 genome AF: 0.696 AC: 105874 AN: 152080 Hom.: 38358 Cov.: 32 AF XY: 0.694 AC XY: 51596 AN XY: 74332

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.661

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.649

Alfa AF: 0.649 Hom.: 16063

Bravo AF: 0.715

Asia WGS AF: 0.769 AC: 2675 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 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	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 04, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.010
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: rs6599250; hg19: chr3-38784029;