Genetic Variant ENST00000415950.5:c.749G>A (chr19-35034040-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000415950.5(SCN1B):c.749G>A(p.Arg250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,550,376 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R250T) has been classified as Benign. The gene SCN1B is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 6 hom. )

Consequence

SCN1B
ENST00000415950.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.409

Publications

31 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

Specifications for SCN1B are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056346953).

BP6

Variant 19-35034040-G-A is Benign according to our data. Variant chr19-35034040-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00023 (35/152124) while in subpopulation SAS AF = 0.00355 (17/4786). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000415950.5. 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+301G>A		intron	N/A	NP_001028.1	Q07699-1
SCN1B	NM_199037.5		c.749G>A	p.Arg250Lys	missense	Exon 3 of 3	NP_950238.1	Q07699-2
SCN1B	NM_001321605.2		c.349+301G>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.749G>A	p.Arg250Lys	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+301G>A		intron	N/A	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000638536.1	TSL:1	c.448+301G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00355

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000795

AC:

123

AN:

154732

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000131

Gnomad NFE exome

AF:

0.0000665

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000375

AC:

524

AN:

1398252

Hom.:

Cov.:

AF XY:

0.000526

AC XY:

363

AN XY:

689732

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31574

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00496

AC:

393

AN:

79214

European-Finnish (FIN)

AF:

0.000304

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1077914

Other (OTH)

AF:

0.000276

AC:

AN:

57956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000230

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41542

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00355

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000400

Hom.:

298

ExAC

AF:

0.00128

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome 5 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.30

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.70

PhyloP100

0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

0.040

REVEL

Benign

0.066

Sift

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.13

MVP

0.84

MPC

0.81

ClinPred

0.047

GERP RS

1.8

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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