Genetic Variant ENST00000415950.5:c.641G>A (chr19-35033932-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 ENST00000415950.5(SCN1B):c.641G>A(p.Arg214Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,559,664 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. R214W) has been classified as Uncertain significance. The gene SCN1B is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 8 hom. )

Consequence

SCN1B
ENST00000415950.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:12O:1

Conservation

PhyloP100: -0.828

Publications

32 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005021572).

BP6

Variant 19-35033932-G-A is Benign according to our data. Variant chr19-35033932-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190847.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00219 (334/152296) while in subpopulation NFE AF = 0.00382 (260/68026). AF 95% confidence interval is 0.00344. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 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+193G>A		intron	N/A	NP_001028.1	Q07699-1
SCN1B	NM_199037.5		c.641G>A	p.Arg214Gln	missense	Exon 3 of 3	NP_950238.1	Q07699-2
SCN1B	NM_001321605.2		c.349+193G>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.641G>A	p.Arg214Gln	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+193G>A		intron	N/A	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000638536.1	TSL:1	c.448+193G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

334

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00382

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00236

AC:

388

AN:

164114

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000458

Gnomad AMR exome

AF:

0.000597

Gnomad ASJ exome

AF:

0.000231

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00413

Gnomad NFE exome

AF:

0.00423

Gnomad OTH exome

AF:

0.00306

GnomAD4 exome

AF:

0.00315

AC:

4437

AN:

1407368

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

2091

AN XY:

695134

show subpopulations

African (AFR)

AF:

0.000470

AC:

AN:

31882

American (AMR)

AF:

0.000554

AC:

AN:

36126

Ashkenazi Jewish (ASJ)

AF:

0.000435

AC:

AN:

25262

East Asian (EAS)

AF:

0.00

AC:

AN:

36118

South Asian (SAS)

AF:

0.000521

AC:

AN:

80662

European-Finnish (FIN)

AF:

0.00359

AC:

179

AN:

49914

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00371

AC:

4015

AN:

1083326

Other (OTH)

AF:

0.00247

AC:

144

AN:

58378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

257

513

770

1026

1283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00219

AC:

334

AN:

152296

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41562

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00382

AC:

260

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00294

Hom.:

Bravo

AF:

0.00222

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

not specified (6)

Brugada syndrome 5 (2)

Atrial fibrillation, familial, 13 (1)

Developmental and epileptic encephalopathy, 52 (1)

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

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

PhyloP100

-0.83

gMVP

0.13

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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