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rs149868494

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

10
9

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]

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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=3, Benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN4BNM_174934.4 linkuse as main transcriptc.22G>A p.Gly8Ser missense_variant 1/5 ENST00000324727.9
SCN4BNM_001142348.2 linkuse as main transcriptc.22G>A p.Gly8Ser missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN4BENST00000324727.9 linkuse as main transcriptc.22G>A p.Gly8Ser missense_variant 1/51 NM_174934.4 P1Q8IWT1-1
SCN4BENST00000529878.1 linkuse as main transcriptc.22G>A p.Gly8Ser missense_variant 1/34 Q8IWT1-3

Frequencies

GnomAD3 genomes
AF:
0.000144
AC:
22
AN:
152256
Hom.:
0
Cov.:
32
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.:
1
AF XY:
0.000419
AC XY:
56
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.:
2
Cov.:
31
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:
22
AN:
152374
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
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.:
0
Bravo
AF:
0.000215
ExAC
AF:
0.000429
AC:
52
Asia WGS
AF:
0.00115
AC:
4
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 submitterclinical testingGeneDxFeb 11, 2021This variant is associated with the following publications: (PMID: 31020414, 30821358) -
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 06, 2017Variant 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. -
not specified Benign:1
Benign, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityMay 26, 2015Note 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. -
SCN4B-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 01, 2019This 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). -
Long QT syndrome 10 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeApr 07, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2016This alteration is classified as likely benign based on a combination of the following: 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
0.19
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
0.010
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.26
T;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.54
T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.0083
T;T
MetaSVM
Uncertain
0.59
D
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
0.97
N;N
PrimateAI
Uncertain
0.63
T
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
T
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.

Other links and lift over

dbSNP: rs149868494; hg19: chr11-118023367; API