chr19-35039140-G-C

Position:

chr19-35039140-G-C

Variant summary

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

The NM_001037.5(SCN1B):c.472G>C(p.Val158Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 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: 0.000012 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 2.67

Variant links:

Genes affected

SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

SCN1B links:

SCN1B (HGNC:):

SCN1B 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=0.17297646).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5 linkuse as main transcript	c.472G>C	p.Val158Leu	missense_variant	4/6	ENST00000262631.11	NP_001028.1	Q07699-1
SCN1B	NM_001321605.2 linkuse as main transcript	c.373G>C	p.Val125Leu	missense_variant	4/6		NP_001308534.1	Q07699A0A1W2PR05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 linkuse as main transcript	c.472G>C	p.Val158Leu	missense_variant	4/6	1	NM_001037.5	ENSP00000262631.3		Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000199

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

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:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727234

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

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:

0.0000675

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	Reported previously in a patient with rolandic epilepsy (RE); however, no further clinical or segregation information was provided (PMID: 29358611); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 29758173, 29358611) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SCN1B: PM5, PP3 -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Brugada syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 433138). This missense change has been observed in individual(s) with clinical features of SCN1B-related conditions (PMID: 29358611). This variant is present in population databases (rs138450474, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 158 of the SCN1B protein (p.Val158Leu). The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.3:c.*5042G>C in the primary transcript. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 18, 2019

ACMG classification criteria: PM2, PM3 -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The p.V158L variant (also known as c.472G>C), located in coding exon 4 of the SCN1B gene, results from a G to C substitution at nucleotide position 472. The valine at codon 158 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in an individual with rolandic or atypical rolandic epilepsy (Bobbili DR et al. Eur. J. Hum. Genet., 2018 02;26:258-264). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of Brugada syndrome; however, its contribution to the development of SCN1B-related developmental and epileptic encephalopathy and SCN1B-related epilepsy is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.66

N;N;.;.

PROVEAN

Benign

-0.60

N;.;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.28

T;.;.;.

Sift4G

Benign

0.33

T;.;T;.

Polyphen

0.11

B;B;B;.

Vest4

0.15

MutPred

0.28

Loss of catalytic residue at V158 (P = 0.0084);Loss of catalytic residue at V158 (P = 0.0084);.;.;

MVP

0.90

ClinPred

0.24

GERP RS

4.1

Varity_R

0.18

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