NM_001037.5:c.28G>A

Variant names:

Variant summary

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

The NM_001037.5(SCN1B):c.28G>A(p.Gly10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 968,158 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. G10D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 6 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -0.213

Publications

4 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=0.0072039366).

BP6

Variant 19-35030848-G-A is Benign according to our data. Variant chr19-35030848-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190869.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00223 (334/149682) while in subpopulation AFR AF = 0.00771 (318/41254). AF 95% confidence interval is 0.00701. There are 6 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,Unknown,AR gene

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.28G>A	p.Gly10Ser	missense	Exon 1 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.28G>A	p.Gly10Ser	missense	Exon 1 of 3	NP_950238.1	Q07699-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.28G>A	p.Gly10Ser	missense	Exon 1 of 6	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000415950.5	TSL:1	c.28G>A	p.Gly10Ser	missense	Exon 1 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000638536.1	TSL:1	c.28G>A	p.Gly10Ser	missense	Exon 1 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

332

AN:

149576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00768

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.00169

AC:

AN:

592

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00962

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

151

AN:

818476

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

392200

show subpopulations

African (AFR)

AF:

0.00876

AC:

137

AN:

15640

American (AMR)

AF:

0.000689

AC:

AN:

4352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8052

East Asian (EAS)

AF:

0.00

AC:

AN:

12188

South Asian (SAS)

AF:

0.00

AC:

AN:

22104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1964

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

710168

Other (OTH)

AF:

0.000302

AC:

AN:

29818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00223

AC:

334

AN:

149682

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

161

AN XY:

73042

show subpopulations

African (AFR)

AF:

0.00771

AC:

318

AN:

41254

American (AMR)

AF:

0.000862

AC:

AN:

15074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5096

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67040

Other (OTH)

AF:

0.00144

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000143

Hom.:

ExAC

AF:

0.0000556

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Brugada syndrome 5 (2)

not provided (2)

Cardiovascular phenotype (1)

Generalized epilepsy with febrile seizures plus, type 1 (1)

SCN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.068

Eigen

Benign

0.017

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

0.0

PhyloP100

-0.21

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.65

REVEL

Benign

0.25

Sift

Benign

0.36

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.094

MutPred

0.36

Loss of sheet (P = 0.0228)

MVP

0.97

MPC

0.67

ClinPred

0.11

GERP RS

2.0

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.067

gMVP

0.52

Mutation Taster

=98/2

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