Variant 11-118137118-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_174934.4(SCN4B):c.596A>G(p.Lys199Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,458,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K199K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN4B
NM_174934.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26489544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCN4B	NM_174934.4 linkuse as main transcript	c.596A>G	p.Lys199Arg	missense_variant, splice_region_variant	5/5	ENST00000324727.9
SCN4B	NM_001142349.2 linkuse as main transcript	c.266A>G	p.Lys89Arg	missense_variant, splice_region_variant	4/4
SCN4B	NM_001142348.2 linkuse as main transcript	c.194A>G	p.Lys65Arg	missense_variant, splice_region_variant	3/3
SCN4B	NR_024527.2 linkuse as main transcript	n.585A>G		splice_region_variant, non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4B	ENST00000324727.9 linkuse as main transcript	c.596A>G	p.Lys199Arg	missense_variant, splice_region_variant	5/5	1	NM_174934.4	P1	Q8IWT1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251298

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135826

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458460

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725746

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 199 of the SCN4B protein (p.Lys199Arg). This variant is present in population databases (rs758628437, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 403961). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

0.096

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

T;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.26

T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

N;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.022

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.23

MutPred

0.20

Loss of methylation at K199 (P = 0.0058);.;

MVP

0.85

MPC

0.44

ClinPred

0.57

GERP RS

4.5

Varity_R

0.15

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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