dbSNP rs554201948: SCN1B:p.Ala197Asp (chr19-35039258-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001037.5(SCN1B):c.590C>A(p.Ala197Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A197V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense, splice_region

Scores

Splicing: ADA: 0.06650

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.50

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.590C>A	p.Ala197Asp	missense splice_region	Exon 4 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_001321605.2		c.491C>A	p.Ala164Asp	missense splice_region	Exon 4 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.590C>A	p.Ala197Asp	missense splice_region	Exon 4 of 6	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000638536.1	TSL:1	c.590C>A	p.Ala197Asp	missense splice_region	Exon 4 of 5	ENSP00000492022.1	Q07699-1
SCN1B	ENST00000675741.1		c.617C>A	p.Ala206Asp	missense splice_region	Exon 4 of 6	ENSP00000502395.1	A0A6Q8PGS1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460434

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Brugada syndrome 5 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.60

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

0.96

Vest4

0.68

MutPred

0.40

Gain of sheet (P = 0.0011)

MVP

0.99

ClinPred

0.91

GERP RS

4.1

Varity_R

0.64

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.067

dbscSNV1_RF

Benign

0.45

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