19-35039258-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001037.5(SCN1B):c.590C>T(p.Ala197Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense, splice_region

Scores

Splicing: ADA: 0.5640

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000116 (17/1460434) while in subpopulation AFR AF= 0.000179 (6/33480). AF 95% confidence interval is 0.0000771. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5 link	c.590C>T	p.Ala197Val	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000262631.11	NP_001028.1	Q07699-1
SCN1B	NM_001321605.2 link	c.491C>T	p.Ala164Val	missense_variant, splice_region_variant	Exon 4 of 6		NP_001308534.1	Q07699A0A1W2PR05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 link	c.590C>T	p.Ala197Val	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_001037.5	ENSP00000262631.3		Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250132

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460434

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Nov 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28341588, 34038903, 34572065, 24324597, 34628405, 32192759, 29758173) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN1B: PM5, PP3 -

Brugada syndrome 5

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.3:c.*5160C>T in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 197 of the SCN1B protein (p.Ala197Val). This variant is present in population databases (rs554201948, gnomAD 0.006%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 29758173, 32192759). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SCN1B function (PMID: 32192759). 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. -

Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52

Uncertain:1

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SCN1B-related disorder

Uncertain:1

Sep 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN1B c.590C>T variant is predicted to result in the amino acid substitution p.Ala197Val. This variant was reported in two individuals with Brugada syndrome or cardiac arrest (Gray et al. 2018. PubMed ID: 29758173; Wang et al. 2020. PubMed ID: 32192759; Zhu et al. 2021. PubMed ID: 34628405). Functional studies suggested that this variant could impact normal protein function (Wang et al. 2020. PubMed ID: 32192759; Zhu et al. 2021. PubMed ID: 34628405). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35530162-C-T) and is interpreted as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/190874/). A different nucleotide substitution affecting the same amino acid (p.Ala197Asp) has been reported in an individual with Brugada syndrome (Ricci et al. 2014. PubMed ID: 25253298). At this time, the clinical significance of the c.590C>T (p.Ala197Val) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A197V variant (also known as c.590C>T), located in coding exon 4 of the SCN1B gene, results from a C to T substitution at nucleotide position 590. The amino acid change results in alanine to valine at codon 197, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 52

Benign:1

Sep 20, 2024

3billion

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Uncertain

0.29

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.9

L;L;.;.

PROVEAN

Uncertain

-2.4

N;.;.;.

REVEL

Pathogenic

0.67

Sift

Benign

0.050

D;.;.;.

Sift4G

Benign

0.079

T;.;D;.

Polyphen

1.0

D;D;D;.

Vest4

0.54

MutPred

0.48

Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);.;.;

MVP

0.99

ClinPred

0.53

GERP RS

4.1

Varity_R

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: -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