19-35030875-G-T

Position:

• chr19-35030875-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262631.11(SCN1B):​c.40+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 659,806 control chromosomes in the GnomAD database, including 14,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2955 hom., cov: 31)
  • Exomes 𝑓: 0.21 (11362 hom.)
• Consequence: SCN1B ENST00000262631.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35030875-G-T is Benign according to our data. Variant chr19-35030875-G-T is described in ClinVar as [Benign]. Clinvar id is 93481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35030875-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.40+15G>T		intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.40+15G>T		intron_variant			NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.40+15G>T		intron_variant		1	NM_001037.5	ENSP00000262631	P1
SCN1B	ENST00000415950.5	c.40+15G>T		intron_variant		1		ENSP00000396915
SCN1B	ENST00000638536.1	c.40+15G>T		intron_variant		1		ENSP00000492022	P1
SCN1B	ENST00000595652.5	c.40+15G>T		intron_variant		2		ENSP00000468848

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29144 AN: 149626 Hom.: 2956 Cov.: 31

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.217

GnomAD3 exomes AF: 0.310 AC: 18 AN: 58 Hom.: 2 AF XY: 0.321 AC XY: 9 AN XY: 28

Gnomad ASJ exome AF: 0.500

Gnomad SAS exome AF: 0.500

Gnomad NFE exome AF: 0.296

GnomAD4 exome AF: 0.207 AC: 105364 AN: 510072 Hom.: 11362 Cov.: 7 AF XY: 0.207 AC XY: 50782 AN XY: 245356

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0866

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.195 AC: 29152 AN: 149734 Hom.: 2955 Cov.: 31 AF XY: 0.193 AC XY: 14099 AN XY: 73068

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0505

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.217

Alfa AF: 0.208 Hom.: 404

Bravo AF: 0.195

Asia WGS AF: 0.105 AC: 337 AN: 3200

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 36. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2015	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Brugada syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Generalized epilepsy with febrile seizures plus, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.5
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs72556351; hg19: chr19-35521779;