rs66876876

Positions:

• chr19-35033932-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000262631.11(SCN1B):​c.448+193G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,559,664 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 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: SCN1B ENST00000262631.11 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:12 O:1
• Conservation: PhyloP100: -0.828

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005021572).
• BP6: Variant 19-35033932-G-A is Benign according to our data. Variant chr19-35033932-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190847.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=7, Likely_benign=3, not_provided=1}. Variant chr19-35033932-G-A is described in Lovd as [Benign]. Variant chr19-35033932-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00219 (334/152296) while in subpopulation NFE AF= 0.00382 (260/68026). AF 95% confidence interval is 0.00344. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 334 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+193G>A		intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.641G>A	p.Arg214Gln	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2	c.349+193G>A		intron_variant			NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+193G>A		intron_variant		1	NM_001037.5	ENSP00000262631	P1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00236 AC: 388 AN: 164114 Hom.: 0 AF XY: 0.00234 AC XY: 204 AN XY: 87182

Gnomad AFR exome AF: 0.000458

Gnomad AMR exome AF: 0.000597

Gnomad ASJ exome AF: 0.000231

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000416

Gnomad FIN exome AF: 0.00413

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00306

GnomAD4 exome AF: 0.00315 AC: 4437 AN: 1407368 Hom.: 8 Cov.: 33 AF XY: 0.00301 AC XY: 2091 AN XY: 695134

Gnomad4 AFR exome AF: 0.000470

Gnomad4 AMR exome AF: 0.000554

Gnomad4 ASJ exome AF: 0.000435

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000521

Gnomad4 FIN exome AF: 0.00359

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74478

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00350 Hom.: 0

Bravo AF: 0.00222

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000806 AC: 2

ESP6500EA AF: 0.00469 AC: 21

ExAC AF: 0.00250 AC: 270

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:6 Other:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SCN1B: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	This variant is associated with the following publications: (PMID: 22155598, 21994374, 22155597, 23465283, 22840528, 27711072, 28837624, 25253298, 23861362, 24055113, 22284586, 23414114, 28341588, 29758173, 29740331, 27435932, 31043699) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The SCN1B c.641G>A, p.Arg214Gln variant (rs66876876) is reported in the literature in three individuals affected with atrial fibrillation (Husser 2017). This variant is also reported in ClinVar (Variation ID: 190847). This variant is found in the general population with an overall allele frequency of 0.2% (461/195480 alleles) in the Genome Aggregation Database. The arginine at codon 214 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.06). However, this missense variant may impact splicing by creating a novel cryptic acceptor splice site/weakening the nearby canonical splice site. Due to limited information, the clinical significance of the p.Arg214Gln variant is uncertain at this time. References: Husser et al. Rare variants in genes encoding the cardiac sodium channel and associated compounds and their impact on outcome of catheter ablation of atrial fibrillation. PLoS One. 2017 Aug 24;12(8):e0183690. PMID 28837624 Gene statement: Pathogenic variants in SCN1B are associated with autosomal dominant familial atrial fibrillation 13 (MIM: 615377), Brugada syndrome 5 (MIM: 612838), nonspecific cardiac conduction defect (MIM: 612838), generalized epilepsy with febrile seizures type 1 (MIM: 604233), and autosomal recessive early infantile epileptic encephalopathy 52 (MIM: 617350). -

not specified Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.4% (5/344) Finnish chromosomes -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2019	Variant summary: SCN1B c.641G>A (p.Arg214Gln, also known as c.448+193G>A based on NM_001037) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 166160 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 420 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.641G>A has been reported in the literature in multiple individuals affected with Brugada syndrome, sudden infant death syndrome, and lone atrial fibrillation (Hu_2012, Crotti_2012, Holst_2012, Olesen_2012, Gray_2018, Husser_2017, Methner_2016, Ng_2013, Nunn_2016, Proost_2017, Ricci_2014). An internal sample reports the variant to co-occur with a likely pathogenic SCN5A variant, c.1338+2T>A. A function study, Hu_2012, indicates the variant decreases sodium current density. Authors have suggested the variant to be a functional polymorphism. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as twice as benign, four as likely benign, and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 04, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg214Gln (c.641 G>A) in the SCN1B gene: The missense p.Arg214Gln variant has been previously reported in six unrelated individuals with BrS, all of whom are of European descent. Hu et al. reported it in two unrelated individuals of European descent with BrS and one child who died from SIDS (Hu et al, 2012) from a cohort of 476 (frequency 0.63%) patients with Brugada syndrome or SIDS. This variant was not seen in 476 ethnically matched controls with BrS, although Hu et al., (2012) did report that this variant had previously been seen in 4 of 807 (frequency 0.49%) ethnically matched controls in a separate dataset. Additionally, it was noted that each of these individuals also had one common polymorphism in the SCN1B gene (L210P, S248R and R250T). This variant was thought to interfere with sodium current density (Hu et al., 2012). This variant has also been reported in one Danish patient from a cohort of 42 (frequency 2.38%) Danish individuals with BrS (Holst et al., 2012). This affected individual did not have any other family members with BrS and segregation data was not available. The variant was absent in 216 ethnically similar controls in this study. This p.Arg214Gln variant has also been seen in a single patient from a cohort of 129 (frequency 0.77%) American and Italian patients with BrS (Crotti et al., 2012). It was seen in one individual in a cohort of 145 (frequency 0.69%) Italian patients with BrS (Ricci et al., 2014). Finally, this variant was seen in a single individual with BrS from a cohort of 22 (frequency 4.54%) Danish individuals with BrS (Oleson et al., 2012). It was not seen in 216 ethnically matched controls. p.Arg214Gln has also been seen in individuals with epilepsy and AF. It was reported in one patient with epilepsy out of a cohort of 360 (frequency 0.27%) American individuals with epilepsy (Patino et al., 2011). It was also seen in two individuals with AF in Denmark. This variant was not seen in 216 ethnically similar controls in this study (Oleson et al., 2012). The p.Arg214Gln variant results in a semi-conservative amino acid change from a positively charged Arginine to a polar Glutamine. The UCSC Genome Browser indicates that the Arginine amino acid is highly conserved from humans to primates. It is not conserved in all vertebrates. Glutamine is in fact the default amino acid in mice, rat & elephant. Additionally, the amino acids surrounding this Arginine are highly conserved through primates but not through all vertebrates. In silico analysis with Polyphen-2, SIFT and Mutation Taster are all consistent and predict this variant to be benign. In total, this variant has been seen in 27 out of ~5,200 controls (1,700 from published literature described above and 3,500 from NHLBI). The NHLBI Exome Sequencing Project dataset currently includes variant calls on 2,237 Caucasian and 1,241 African American individuals for this variant (as of 10/23/14). This variant was seen in a total of 21 European American individuals and 2 African American individuals (overall frequency 0.66%, Caucasian frequency almost 1%). There is no variation at this codon listed in 1000 genomes (as of 10/23/14). Variation at this codon is seen in the ExAC Browser dataset, which currently includes variant calls on 26,976 individuals of multiple ethnic backgrounds. It is particularly frequent among Caucasians. This variant was seen in a total of 87 individuals of Finnish(6), European(76), Latino(2), African(1) and South Asian(2) descent (frequency 0.33%) (as of 10/23/14). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 29, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Brugada syndrome 5 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

Atrial fibrillation, familial, 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Developmental and epileptic encephalopathy, 52 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.3
DANN	Benign	0.97
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	0.31	N;.
REVEL	Benign	0.062
Sift	Benign	0.34	T;.
Polyphen		0.017	B;.
Vest4		0.14
MVP		0.79
MPC		0.84
ClinPred		0.0019	T
GERP RS		0.78
gMVP		0.13

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: rs66876876; hg19: chr19-35524836; COSMIC: COSV99386640; COSMIC: COSV99386640;