19-35033851-G-A

Position:

chr19-35033851-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000262631.11(SCN1B):c.448+112G>A variant causes a intron 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 9 hom. )

Consequence

SCN1B
ENST00000262631.11 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 180509.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN1B	NM_001037.5 linkuse as main transcript	c.448+112G>A		intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5 linkuse as main transcript	c.560G>A	p.Arg187His	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2 linkuse as main transcript	c.349+112G>A		intron_variant			NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 linkuse as main transcript	c.448+112G>A		intron_variant		1	NM_001037.5	ENSP00000262631	P1	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

GnomAD3 exomes

AF:

0.00149

AC:

364

AN:

244964

Hom.:

AF XY:

0.00142

AC XY:

189

AN XY:

133376

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 SAS exome

AF:

0.0000328

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

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000898

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0128

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000684

AC:

104

AN:

152138

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0183

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000790

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: SCN1B c.560G>A (p.Arg187His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 271814 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 137-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1B causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. The variant, c.560G>A, has been reported in the literature in individuals affected with idiopathic cardiac arrest and one patient with cardiopulmonary arrest and Brugada-pattern electrocardiogram (Mellor_2017, Nakajima_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ventricular fibrillation

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 26, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Brugada syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.48

DANN

Uncertain

0.99

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.47

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.15

N;.

REVEL

Benign

0.061

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0010

B;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over