rs145313578

Positions:

• chr3-38697925-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.5295G>A​(p.Ser1765Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,978 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.69

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 3-38697925-C-T is Benign according to our data. Variant chr3-38697925-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 381215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38697925-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS2: High AC in GnomAd4 at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.5295G>A	p.Ser1765Ser	synonymous_variant	28/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.5295G>A	p.Ser1765Ser	synonymous_variant	28/28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.5292G>A	p.Ser1764Ser	synonymous_variant	27/27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.5319G>A	p.Ser1773Ser	synonymous_variant	28/28			ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 251134 Hom.: 0 AF XY: 0.00104 AC XY: 141 AN XY: 135698

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00114 AC: 1661 AN: 1461892 Hom.: 3 Cov.: 32 AF XY: 0.00113 AC XY: 820 AN XY: 727246

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74336

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000997

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	SCN10A: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 28, 2024

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2019

This alteration is classified as likely 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	5.6
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145313578; hg19: chr3-38739416; COSMIC: COSV71860935;