rs144944369

chr3-38702080-G-Achr3-38702080-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006514.4(SCN10A):c.4416C>T(p.Ile1472=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,572,562 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 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0620

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-38702080-G-A is Benign according to our data. Variant chr3-38702080-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 414630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38702080-G-A is described in Lovd as [Benign]. Variant chr3-38702080-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.062 with no splicing effect.
• BS2: High AC in GnomAd at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.4416C>T	p.Ile1472=	synonymous_variant	27/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.4416C>T	p.Ile1472=	synonymous_variant	27/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.4440C>T	p.Ile1480=	synonymous_variant	27/28
SCN10A	ENST00000643924.1	c.4413C>T	p.Ile1471=	synonymous_variant	26/27			A1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00106 AC: 229 AN: 215072 Hom.: 0 AF XY: 0.000982 AC XY: 113 AN XY: 115082

Gnomad AFR exome AF: 0.000896

Gnomad AMR exome AF: 0.000431

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000931

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00103 AC: 1466 AN: 1420240 Hom.: 3 Cov.: 31 AF XY: 0.00104 AC XY: 729 AN XY: 702332

Gnomad4 AFR exome AF: 0.000376

Gnomad4 AMR exome AF: 0.000545

Gnomad4 ASJ exome AF: 0.000126

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000905

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74480

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SCN10A: BP4, BP7 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Episodic pain syndrome, familial, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 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	-0.39
Cadd	Benign	4.6
Dann	Benign	0.67

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: rs144944369; hg19: chr3-38743571; COSMIC: COSV104716772;