Genetic Variant SCN1B:p.Arg3Thr (chr19-35030828-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001037.5(SCN1B):c.8G>C(p.Arg3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0240

Publications

0 publications found

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:

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

HPN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14800426).

BP6

Variant 19-35030828-G-C is Benign according to our data. Variant chr19-35030828-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3438196.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5 link	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1	Q07699-1
SCN1B	NM_199037.5 link	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 3		NP_950238.1	Q07699-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 link	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3		Q07699-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

938412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

457982

African (AFR)

AF:

0.00

AC:

AN:

17450

American (AMR)

AF:

0.00

AC:

AN:

6966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10160

East Asian (EAS)

AF:

0.00

AC:

AN:

13662

South Asian (SAS)

AF:

0.00

AC:

AN:

39656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

795540

Other (OTH)

AF:

0.00

AC:

AN:

34434

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Benign:1

Oct 22, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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

0.064

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.051

T;T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.45

.;T;T;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

-0.020

MutationAssessor

Benign

0.0

N;N;N;.

PhyloP100

0.024

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.81

N;.;N;.

REVEL

Benign

0.22

Sift

Benign

0.58

T;.;T;.

Sift4G

Benign

0.48

T;.;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.13

MutPred

0.35

Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);

MVP

0.89

MPC

0.98

ClinPred

0.027

GERP RS

0.0044

PromoterAI

0.012

Neutral

(source)

Varity_R

0.044

gMVP

0.54

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over