chr11-118152652-C-T

Position:

chr11-118152652-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_174934.4(SCN4B):c.22G>A(p.Gly8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,611,590 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

SCN4B
NM_174934.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.57

Variant links:

Genes affected

SCN4B (HGNC:10592): (sodium voltage-gated channel beta subunit 4) The protein encoded by this gene is one of several sodium channel beta subunits. These subunits interact with voltage-gated alpha subunits to change sodium channel kinetics. The encoded transmembrane protein forms interchain disulfide bonds with SCN2A. Defects in this gene are a cause of long QT syndrome type 10 (LQT10). Three protein-coding and one non-coding transcript variant have been found for this gene.[provided by RefSeq, Mar 2009]

SCN4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008304477).

BP6

Variant 11-118152652-C-T is Benign according to our data. Variant chr11-118152652-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4B	NM_174934.4 linkuse as main transcript	c.22G>A	p.Gly8Ser	missense_variant	1/5	ENST00000324727.9
SCN4B	NM_001142348.2 linkuse as main transcript	c.22G>A	p.Gly8Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4B	ENST00000324727.9 linkuse as main transcript	c.22G>A	p.Gly8Ser	missense_variant	1/5	1	NM_174934.4	P1	Q8IWT1-1
SCN4B	ENST00000529878.1 linkuse as main transcript	c.22G>A	p.Gly8Ser	missense_variant	1/3	4			Q8IWT1-3

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

152256

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:

0.00404

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000407

AC:

100

AN:

245432

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

133758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00482

Gnomad SAS exome

AF:

0.000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000912

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000214

AC:

312

AN:

1459216

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

725532

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00674

Gnomad4 SAS exome

AF:

0.000337

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000144

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00405

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000391

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000429

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2021	This variant is associated with the following publications: (PMID: 31020414, 30821358) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2017	Variant summary: The SCN4B c.22G>A (p.Gly8Ser) variant involves the alteration of a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, however, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 52/109666 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.005546 (46/8294). This frequency is about 555 times the estimated maximal expected allele frequency of a pathogenic SCN4B variant (0.00001), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Therefore, the variant of interest has been classified as Benign. -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 26, 2015

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly8Ser (c.22G>A) in SCN4B. The variant was reported online in 52 of 54,833 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of May 26, 2015). Specifically, the variant was observed in 46 of 4147 East Asian individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Long QT syndrome 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2016

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. -

SCN4B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.54

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0083

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.97

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.73

N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.024

D;T

Sift4G

Benign

0.26

T;.

Polyphen

0.94

P;.

Vest4

0.33

MVP

0.76

MPC

0.27

ClinPred

0.067

GERP RS

3.7

Varity_R

0.096

gMVP

0.72

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