rs121918282

Positions:

chr11-123653773-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001040151.2(SCN3B):c.29T>C(p.Leu10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

SCN3B
NM_001040151.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:1O:1

Conservation

PhyloP100: 0.766

Variant links:

Genes affected

SCN3B (HGNC:20665): (sodium voltage-gated channel beta subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel beta subunit gene family, and influences the inactivation kinetics of the sodium channel. Two alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

SCN3B links:

LOC105369543 (HGNC:):

LOC105369543 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29861468).

BS2

High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCN3B	NM_001040151.2 linkuse as main transcript	c.29T>C	p.Leu10Pro	missense_variant	2/7	ENST00000299333.8
LOC105369543	XR_948124.4 linkuse as main transcript	n.89A>G		non_coding_transcript_exon_variant	1/3
SCN3B	NM_018400.4 linkuse as main transcript	c.29T>C	p.Leu10Pro	missense_variant	1/6
SCN3B	XM_011542897.3 linkuse as main transcript	c.29T>C	p.Leu10Pro	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3B	ENST00000299333.8 linkuse as main transcript	c.29T>C	p.Leu10Pro	missense_variant	2/7	1	NM_001040151.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251474

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000434

AC:

635

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

285

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000531

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000335

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 7

Pathogenic:2Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 10 of the SCN3B protein (p.Leu10Pro). This variant is present in population databases (rs121918282, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of SCN3B-related conditions (PMID: 20031595, 21051419, 22284586, 25650408, 25757662, 29247119, 31043699). ClinVar contains an entry for this variant (Variation ID: 2470). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN3B function (PMID: 20031595, 21051419, 23257389). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, flagged submission	literature only	OMIM	Mar 01, 2011	- -
Likely pathogenic, flagged submission	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 24667784, 22284586, 25757662, 23414114, 24055113, 24144883, 26728597, 25668026, 20031595, 25650408, 21051419, 25691686, 20558140, 36362949, 34572065, 35083300, 31961030, 35385795, 35456365, LauK2016[Abstract], 32684122, 36354758, 34495297, 23257389, 34867379, 30821013, 31019283, 31043699, 29247119) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 28, 2021	- -

Atrial fibrillation, familial, 16

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Mar 01, 2011

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 23, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Leu10Pro vari ant in SCN3B has been reported in 1 individual with Brugada syndrome and 1 indiv idual with atrial fibrillation (Hu 2009, Olesen 2011, Olesen 2014). In addition, this variant has been identified in 19/66726 of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP 12191828 2). In vitro functional studies provide some evidence that this variant may impa ct protein function (Hu 2009, Olesen 201), though these types of assays may not accurately represent biological function. Leucine (Leu) at position 10 is not co nserved in mammals with 3 mammals (gibbon, hedgehog, and shrew) carrying a proli ne (Pro) at this position, raising the possibility that this change may be toler ated. In summary, although the clinical significance of the p.Leu10Pro variant is uncertain it is less likely disease causing. -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2022

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

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;T;T;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.082

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.30

T;T;T;T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.3

L;L;L;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.091

T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;.;.

Polyphen

0.026

B;B;B;.;.

Vest4

0.42

MVP

0.82

MPC

0.71

ClinPred

0.057

GERP RS

2.5

Varity_R

0.31

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over