rs34314583

Positions:

• chr3-38793966-G-A

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.45C>T​(p.Arg15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,613,980 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (91 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.03

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=-0.47).
• BP6: Variant 3-38793966-G-A is Benign according to our data. Variant chr3-38793966-G-A is described in ClinVar as [Benign]. Clinvar id is 240676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38793966-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS2: High AC in GnomAd4 at 984 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.45C>T	p.Arg15=	synonymous_variant	2/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.45C>T	p.Arg15=	synonymous_variant	2/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.45C>T	p.Arg15=	synonymous_variant	2/28
SCN10A	ENST00000643924.1	c.45C>T	p.Arg15=	synonymous_variant	1/27			A1

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 985 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00587 AC: 1473 AN: 250830 Hom.: 8 AF XY: 0.00558 AC XY: 756 AN XY: 135530

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00885

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00856 AC: 12508 AN: 1461670 Hom.: 91 Cov.: 31 AF XY: 0.00839 AC XY: 6100 AN XY: 727144

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.00646 AC: 984 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00635 AC XY: 473 AN XY: 74484

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00831 Hom.: 1

Bravo AF: 0.00539

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00842

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

SCN10A: BP4, BP7, BS1, BS2 -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 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	-0.47
CADD	Benign	6.5
DANN	Benign	0.54

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: rs34314583; hg19: chr3-38835457;