rs28365109

Positions:

• chr19-35039621-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001037.5(SCN1B):​c.591-14C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,010 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (182 hom.)
• Consequence: SCN1B NM_001037.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.00600

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=-0.7).
• BP6: Variant 19-35039621-C-A is Benign according to our data. Variant chr19-35039621-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 257220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35039621-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00951 (1448/152300) while in subpopulation SAS AF= 0.0191 (92/4824). AF 95% confidence interval is 0.0159. There are 15 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1448 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.591-14C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_001321605.2	c.492-14C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.591-14C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001037.5	ENSP00000262631	P1

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1445 AN: 152182 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0112 AC: 2822 AN: 251362 Hom.: 32 AF XY: 0.0123 AC XY: 1673 AN XY: 135874

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0199

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0144 AC: 21009 AN: 1461710 Hom.: 182 Cov.: 31 AF XY: 0.0147 AC XY: 10662 AN XY: 727168

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.00279

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00951 AC: 1448 AN: 152300 Hom.: 15 Cov.: 32 AF XY: 0.00884 AC XY: 658 AN XY: 74468

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.00884

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 13, 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. -

Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.88

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

Other links and lift over

dbSNP: rs28365109; hg19: chr19-35530525;