rs200761835

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004588.5(SCN2B):c.118G>A(p.Val40Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

SCN2B
NM_004588.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.28

Variant links:

Genes affected

SCN2B (HGNC:10589): (sodium voltage-gated channel beta subunit 2) The protein encoded by this gene is the beta 2 subunit of the type II voltage-gated sodium channel. The encoded protein is involved in cell-cell adhesion and cell migration. Defects in this gene can be a cause of Brugada Syndrome, atrial fibrillation, or sudden infant death syndrome. [provided by RefSeq, Jul 2015]

SCN2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18844536).

BS2

High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2B	NM_004588.5 linkuse as main transcript	c.118G>A	p.Val40Ile	missense_variant	2/4	ENST00000278947.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN2B	ENST00000278947.6 linkuse as main transcript	c.118G>A	p.Val40Ile	missense_variant	2/4	1	NM_004588.5	P1
SCN2B	ENST00000665446.1 linkuse as main transcript	n.354G>A		non_coding_transcript_exon_variant	3/4
SCN2B	ENST00000669850.1 linkuse as main transcript	n.360G>A		non_coding_transcript_exon_variant	2/4
SCN2B	ENST00000658882.1 linkuse as main transcript	c.222G>A	p.Thr74=	synonymous_variant, NMD_transcript_variant	3/5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251472

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 40 of the SCN2B protein (p.Val40Ile). This variant is present in population databases (rs200761835, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 191494). 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 isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The p.V40I variant (also known as c.118G>A), located in coding exon 2 of the SCN2B gene, results from a G to A substitution at nucleotide position 118. The valine at codon 40 is replaced by isoleucine, an amino acid with highly similar properties. This variant co-occurred with variants in other cardiac-related genes in an individual from a Brugada syndrome cohort, and has been reported as a secondary cardiac variant in an exome cohort; however, details were limited (Di Resta C et al. Hum Mol Genet, 2015 Oct;24:5828-35; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated 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

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

M_CAP

Benign

0.019

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

0.87

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.93

REVEL

Benign

0.23

Sift

Benign

0.18

Sift4G

Benign

0.081

Polyphen

0.0080

Vest4

0.094

MVP

0.48

MPC

0.19

ClinPred

0.22

GERP RS

2.3

Varity_R

0.21

gMVP

0.58

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