Genetic Variant SCN1B:p.Arg125Leu (chr19-35033665-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001037.5(SCN1B):c.374G>T(p.Arg125Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.44

Publications

9 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_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001037.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1B	NM_001037.5	MANE Select	c.374G>T	p.Arg125Leu	missense	Exon 3 of 6	NP_001028.1	Q07699-1
SCN1B	NM_199037.5		c.374G>T	p.Arg125Leu	missense	Exon 3 of 3	NP_950238.1	Q07699-2
SCN1B	NM_001321605.2		c.275G>T	p.Arg92Leu	missense	Exon 3 of 6	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.374G>T	p.Arg125Leu	missense	Exon 3 of 6	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000415950.5	TSL:1	c.374G>T	p.Arg125Leu	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000638536.1	TSL:1	c.374G>T	p.Arg125Leu	missense	Exon 3 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Brugada syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

PhyloP100

9.4

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.88

MutPred

0.86

Loss of solvent accessibility (P = 0.1077)

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.98

Mutation Taster

=10/90

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over