rs72558029

Positions:

• chr19-35033703-G-A
• chr19-35033703-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001037.5(SCN1B):​c.412G>A​(p.Val138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,154 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (341 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.94

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 -18 ACMG points.

• PM1: In a domain Ig-like C2-type (size 128) in uniprot entity SCN1B_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001037.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017569363).
• BP6: Variant 19-35033703-G-A is Benign according to our data. Variant chr19-35033703-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35033703-G-A is described in Lovd as [Benign]. Variant chr19-35033703-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.412G>A	p.Val138Ile	missense_variant	3/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.412G>A	p.Val138Ile	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2	c.313G>A	p.Val105Ile	missense_variant	3/6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.412G>A	p.Val138Ile	missense_variant	3/6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152146 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.0103 AC: 2601 AN: 251490 Hom.: 115 AF XY: 0.0136 AC XY: 1850 AN XY: 135920

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00555

Gnomad SAS exome AF: 0.0789

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00517 AC: 7554 AN: 1461890 Hom.: 341 Cov.: 33 AF XY: 0.00725 AC XY: 5272 AN XY: 727244

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00297

Gnomad4 SAS exome AF: 0.0784

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000845

Gnomad4 OTH exome AF: 0.00861

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152264 Hom.: 26 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74440

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00851

Gnomad4 SAS AF: 0.0882

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.00109

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0117 AC: 1418

Asia WGS AF: 0.0550 AC: 189 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Feb 21, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: 28704380, 24529773) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 29, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2015	- -

Brugada syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 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. -

SCN1B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 27, 2015

The SCN1B Val138Ile variant has been previously reported. It is observed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) with an allele frequency of 0.012 (1418/121366 alleles); and the frequency in the South Asian subpopulation is 0.08. In-silico software tools predict this variant to be tolerable (SIFT "tolerated"; PholyPhen2 "benign", MutationTaster "polymorphism"). We identified this variant in a female with an undetermined heart disease, normal echocardiogram, paroxysmal atrial fibrillation and non-sustained ventricular tachycardia. There is no clear family history of disease. Based on the high frequency (>1%) observed in the general population, we have classified this variant as "likely benign". -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T;.;.;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	.;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.45	N;N;N;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.53	N;.;N;.;.
REVEL	Benign	0.26
Sift	Benign	0.40	T;.;T;.;.
Sift4G	Benign	0.64	T;.;T;.;.
Polyphen		0.28	B;B;P;.;.
Vest4		0.041
MPC		0.71
ClinPred		0.0067	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.69

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: rs72558029; hg19: chr19-35524607;