rs6795970

chr3-38725184-A-Gchr3-38725184-A-T

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.3218T>C(p.Val1073Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,594,466 control chromosomes in the GnomAD database, including 318,682 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1073I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.70 (38763 hom., cov: 32)
  • Exomes 𝑓: 0.62 (279919 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.04

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 (MetaRNN=7.03869E-7).
• BP6: Variant 3-38725184-A-G is Benign according to our data. Variant chr3-38725184-A-G is described in ClinVar as [Benign]. Clinvar id is 259996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38725184-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.3218T>C	p.Val1073Ala	missense_variant	18/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.3218T>C	p.Val1073Ala	missense_variant	18/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.3242T>C	p.Val1081Ala	missense_variant	18/28
SCN10A	ENST00000643924.1	c.3215T>C	p.Val1072Ala	missense_variant	17/27			A1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106402 AN: 151966 Hom.: 38689 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.653

GnomAD3 exomes AF: 0.652 AC: 161934 AN: 248186 Hom.: 54207 AF XY: 0.644 AC XY: 86354 AN XY: 134142

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.848

Gnomad SAS exome AF: 0.645

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.619 AC: 893149 AN: 1442382 Hom.: 279919 Cov.: 45 AF XY: 0.618 AC XY: 442210 AN XY: 715412

Gnomad4 AFR exome AF: 0.917

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.851

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.601

Gnomad4 OTH exome AF: 0.632

GnomAD4 genome AF: 0.701 AC: 106542 AN: 152084 Hom.: 38763 Cov.: 32 AF XY: 0.699 AC XY: 51984 AN XY: 74352

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.851

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.605

Gnomad4 OTH AF: 0.655

Alfa AF: 0.622 Hom.: 73971

Bravo AF: 0.719

TwinsUK AF: 0.604 AC: 2239

ALSPAC AF: 0.596 AC: 2297

ESP6500AA AF: 0.899 AC: 3961

ESP6500EA AF: 0.602 AC: 5176

ExAC AF: 0.657 AC: 79802

Asia WGS AF: 0.771 AC: 2681 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 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
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.66
Dann	Benign	0.54
DEOGEN2	Benign	0.031	T;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
MetaRNN	Benign	7.0e-7	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.51	N;.;.;.
REVEL	Benign	0.21
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	1.0	T;.;.;.
Polyphen		0.0	B;.;B;.
Vest4		0.0060
MPC		0.070
ClinPred		0.00070	T
GERP RS		-4.6
Varity_R		0.024
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6795970; hg19: chr3-38766675;