rs72558026

Positions:

• chr19-35033851-G-A

Variant summary

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

The NM_199037.5(SCN1B):​c.560G>A​(p.Arg187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,610,784 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (9 hom.)
• Consequence: SCN1B NM_199037.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.48

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=0.0037579536).
• BP6: Variant 19-35033851-G-A is Benign according to our data. Variant chr19-35033851-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180509.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000684 (104/152138) while in subpopulation EAS AF= 0.0183 (94/5144). AF 95% confidence interval is 0.0153. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+112G>A		intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.560G>A	p.Arg187His	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2	c.349+112G>A		intron_variant			NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+112G>A		intron_variant		1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00149 AC: 364 AN: 244964 Hom.: 5 AF XY: 0.00142 AC XY: 189 AN XY: 133376

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000380 AC: 554 AN: 1458646 Hom.: 9 Cov.: 33 AF XY: 0.000375 AC XY: 272 AN XY: 725324

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000684 AC: 104 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000834 AC XY: 62 AN XY: 74348

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0183

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000790

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2017	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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: SCN1B c.560G>A (p.Arg187His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 271814 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 137-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 benign. The variant, c.560G>A, has been reported in the literature in individuals affected with idiopathic cardiac arrest and one patient with cardiopulmonary arrest and Brugada-pattern electrocardiogram (Mellor_2017, Nakajima_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Ventricular fibrillation Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 26, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Brugada syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.48
DANN	Uncertain	0.99
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.69	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.0010	B;.
Vest4		0.049
MutPred		0.40		Loss of sheet (P = 0.0054);.;
MVP		0.40
MPC		1.8
ClinPred		0.082	T
GERP RS		-3.9
gMVP		0.33

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: rs72558026; hg19: chr19-35524755;