rs17121819

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_004588.5(SCN2B):c.82C>T(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

SCN2B
NM_004588.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.854

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=0.13055259).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2B	NM_004588.5 link	c.82C>T	p.Arg28Trp	missense_variant	Exon 2 of 4	ENST00000278947.6	NP_004579.1	O60939Q5U0K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2B	ENST00000278947.6 link	c.82C>T	p.Arg28Trp	missense_variant	Exon 2 of 4	1	NM_004588.5	ENSP00000278947.5	O60939
SCN2B	ENST00000658882.1 link	n.186C>T		non_coding_transcript_exon_variant	Exon 3 of 5			ENSP00000499572.1	A0A590UJS3
SCN2B	ENST00000665446.1 link	n.318C>T		non_coding_transcript_exon_variant	Exon 3 of 4
SCN2B	ENST00000669850.1 link	n.324C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251286

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 14

Pathogenic:1Uncertain:2

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 28 of the SCN2B protein (p.Arg28Trp). This variant is present in population databases (rs17121819, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 19808477). ClinVar contains an entry for this variant (Variation ID: 60769). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The tryptophan 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 SCN2B function (PMID: 19808477). 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. -

Jun 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Mar 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with paroxsymal atrial fibrillation, right precordial saddleback type ST-segment elevation on ECG, and a history of hypertension in published literature (Watanabe et al., 2009); Published functional studies showed reduced peak sodium current amplitude and a positive shift in the voltage dependence of activation, but no effect on the voltage dependence of inactivation or the persistence of the sodium current compared to wild-type SCN2B (Watanabe et al., 2009); 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: 26986070, 35385795, 34426522, 19808477) -

Cardiovascular phenotype

Benign:1

Nov 21, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.067

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.077

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.080

REVEL

Uncertain

0.56

Sift

Benign

0.042

Sift4G

Benign

0.098

Polyphen

0.83

Vest4

0.21

MVP

0.98

MPC

0.25

ClinPred

0.069

GERP RS

2.7

Varity_R

0.41

gMVP

0.52

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