rs587777555

Positions:

chr11-123645645-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001040151.2(SCN3B):c.161T>G(p.Val54Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

SCN3B
NM_001040151.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3B	NM_001040151.2 linkuse as main transcript	c.161T>G	p.Val54Gly	missense_variant	3/7	ENST00000299333.8	NP_001035241.1	Q9NY72A0A024R3H7
SCN3B	NM_018400.4 linkuse as main transcript	c.161T>G	p.Val54Gly	missense_variant	2/6		NP_060870.1	Q9NY72A0A024R3H7
SCN3B	XM_011542897.3 linkuse as main transcript	c.161T>G	p.Val54Gly	missense_variant	3/7		XP_011541199.1	Q9NY72A0A024R3H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3B	ENST00000299333.8 linkuse as main transcript	c.161T>G	p.Val54Gly	missense_variant	3/7	1	NM_001040151.2	ENSP00000299333.3		Q9NY72

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251410

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000882

AC:

129

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2017	The V54G variant in the SCN3B gene has been reported in one individual with idiopathic ventricular fibrillation and also in this individual's asymptomatic mother (Valdivia C et al., 2010). In addition, the V54G variant has been reported in one case of SIDS and was absent from 800 control alleles (Tan B et al., 2010). Furthermore, the V54G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Moreover, in vitro functional studies show that the V54G variant causes loss of channel function (Valdivia et al., 2010; Tan et al., 2010). However, the V54G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Brugada syndrome 7

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2019	This variant is present in population databases (rs587777555, ExAC 0.003%). 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. This variant has been reported to affect SCN3B protein function (PMID: 20042427, 20226894). This variant has been observed in an individual affected with ventricular fibrillation (PMID: 20042427) and in an individual who suffered sudden unexplained death (PMID: 20226894). ClinVar contains an entry for this variant (Variation ID: 140596). This sequence change replaces valine with glycine at codon 54 of the SCN3B protein (p.Val54Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2022

The p.V54G variant (also known as c.161T>G), located in coding exon 2 of the SCN3B gene, results from a T to G substitution at nucleotide position 161. The valine at codon 54 is replaced by glycine, an amino acid with dissimilar properties. This variant has been reported in an individual with idiopathic ventricular fibrillation and in a sudden infant death case (Valdivia CR et al. Cardiovasc. Res., 2010 Jun;86:392-400; Tan BH et al. Heart Rhythm, 2010 Jun;7:771-8). Limited in vitro studies by these authors suggest that this alteration may impact protein function; however, the clinical implications of these findings are unknown. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D;D;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;T;.;.;.

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.4

M;M;M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;.;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.67

MutPred

0.80

Loss of stability (P = 0.026);Loss of stability (P = 0.026);Loss of stability (P = 0.026);Loss of stability (P = 0.026);Loss of stability (P = 0.026);

MVP

0.99

MPC

1.5

ClinPred

0.89

GERP RS

6.0

Varity_R

0.77

gMVP

0.87

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