dbSNP rs72558026: SCN1B:p.Arg187His (chr19-35033851-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_199037.5(SCN1B):c.560G>A(p.Arg187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,610,784 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. R187C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 9 hom. )

Consequence

SCN1B
NM_199037.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.48

Publications

7 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037579536).

BP6

Variant 19-35033851-G-A is Benign according to our data. Variant chr19-35033851-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180509.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000684 (104/152138) while in subpopulation EAS AF = 0.0183 (94/5144). AF 95% confidence interval is 0.0153. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199037.5. 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.448+112G>A		intron	N/A	NP_001028.1	Q07699-1
SCN1B	NM_199037.5		c.560G>A	p.Arg187His	missense	Exon 3 of 3	NP_950238.1	Q07699-2
SCN1B	NM_001321605.2		c.349+112G>A		intron	N/A	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1B	ENST00000415950.5	TSL:1	c.560G>A	p.Arg187His	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+112G>A		intron	N/A	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000638536.1	TSL:1	c.448+112G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0186

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00149

AC:

364

AN:

244964

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000380

AC:

554

AN:

1458646

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

272

AN XY:

725324

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33432

American (AMR)

AF:

0.0000898

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0128

AC:

508

AN:

39656

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110372

Other (OTH)

AF:

0.000547

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000684

AC:

104

AN:

152138

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41508

American (AMR)

AF:

0.000327

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0183

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000790

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Brugada syndrome 5 (1)

not provided (1)

Ventricular fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.48

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.69

PhyloP100

-1.5

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.15

REVEL

Benign

0.061

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.049

MutPred

0.40

Loss of sheet (P = 0.0054)

MVP

0.40

MPC

1.8

ClinPred

0.082

GERP RS

-3.9

gMVP

0.33

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over