rs786205833

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001037.5(SCN1B):c.23T>C(p.Val8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,007,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V8L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.156

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21743363).

BP6

Variant 19-35030843-T-C is Benign according to our data. Variant chr19-35030843-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190868.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/6	ENST00000262631.11
SCN1B	NM_199037.5 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/6	1	NM_001037.5	P1	Q07699-1
SCN1B	ENST00000415950.5 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/3	1			Q07699-2
SCN1B	ENST00000638536.1 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/5	1		P1	Q07699-1
SCN1B	ENST00000595652.5 linkuse as main transcript	c.23T>C	p.Val8Ala	missense_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

148506

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000449

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

858512

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

413890

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:

0.0000122

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000269

AC:

AN:

148506

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000104

Gnomad4 NFE

AF:

0.0000449

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2023

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. ClinVar contains an entry for this variant (Variation ID: 190868). This missense change has been observed in individual(s) with SCN1B-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 8 of the SCN1B protein (p.Val8Ala). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2022

The p.V8A variant (also known as c.23T>C), located in coding exon 1 of the SCN1B gene, results from a T to C substitution at nucleotide position 23. The valine at codon 8 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.18

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Uncertain

0.093

MutationAssessor

Benign

0.0

N;N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.76

N;.;N;.

REVEL

Benign

0.29

Sift

Benign

0.17

T;.;D;.

Sift4G

Benign

0.37

T;.;D;T

Polyphen

0.019

B;B;B;B

Vest4

0.085

MutPred

0.34

Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.88

MPC

0.81

ClinPred

0.078

GERP RS

2.0

Varity_R

0.091

gMVP

0.55

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