rs66671189

chr19-35030812-C-Achr19-35030812-C-Gchr19-35030812-C-T

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.-9C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,079,936 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: SCN1B NM_001037.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.52

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 19-35030812-C-A is Benign according to our data. Variant chr19-35030812-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 139002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35030812-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00542 (809/149144) while in subpopulation AFR AF= 0.0188 (775/41126). AF 95% confidence interval is 0.0177. There are 6 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 809 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.-9C>A		5_prime_UTR_variant	1/6	ENST00000262631.11
SCN1B	NM_199037.5	c.-9C>A		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.-9C>A		5_prime_UTR_variant	1/6	1	NM_001037.5	P1
SCN1B	ENST00000415950.5	c.-9C>A		5_prime_UTR_variant	1/3	1
SCN1B	ENST00000638536.1	c.-9C>A		5_prime_UTR_variant	1/5	1		P1
SCN1B	ENST00000595652.5	c.-9C>A		5_prime_UTR_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 809 AN: 149042 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00341

GnomAD3 exomes AF: 0.000502 AC: 7 AN: 13934 Hom.: 0 AF XY: 0.000476 AC XY: 4 AN XY: 8396

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000363

Gnomad ASJ exome AF: 0.000772

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000392 AC: 365 AN: 930792 Hom.: 5 Cov.: 13 AF XY: 0.000334 AC XY: 153 AN XY: 458422

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.000488

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000115

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00542 AC: 809 AN: 149144 Hom.: 6 Cov.: 31 AF XY: 0.00514 AC XY: 374 AN XY: 72734

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00146

Gnomad4 ASJ AF: 0.00146

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00337

Alfa AF: 0.0000699 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2015	- -

Brugada syndrome 5 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 06, 2016

Variant summary: This c.-9C>A variant affects a non-conserved nucleotide, located in the 5' UTR, a location that could affect transcription, however, no functional studies have been performed to assess this. The variant of interest was observed in a control population (1000 Gs) with an allele frequency of 38/5008, predominantly in African cohort with an allele frequency of 0.026 (34/1322 chromosomes). This frequency exceeds the predicted maximum expected allele frequency for a pathogenic SCN1B allele (0.00001), suggesting this variant is benign. In addition, Multiple clinical laboratories have classified this variant as benign. Taken together, this variant has been classified as Benign. -

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	6.1
Dann	Benign	0.93

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: rs66671189; hg19: chr19-35521716;