rs180943300

chr19-35032621-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

The NM_001037.5(SCN1B):c.134G>A(p.Arg45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a disulfide_bond (size 81) in uniprot entity SCN1B_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_001037.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.16521382).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000171 (25/1461796) while in subpopulation AMR AF= 0.000291 (13/44724). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.134G>A	p.Arg45His	missense_variant	2/6	ENST00000262631.11
SCN1B	NM_199037.5	c.134G>A	p.Arg45His	missense_variant	2/3
SCN1B	NM_001321605.2	c.35G>A	p.Arg12His	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.134G>A	p.Arg45His	missense_variant	2/6	1	NM_001037.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251352 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 45 of the SCN1B protein (p.Arg45His). This variant is present in population databases (rs180943300, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 190857). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2019

A variant of uncertain significance has been identified in the SCN1B gene. The R45H variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 3/34418 (0.02%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016). The R45H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support adeleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2023

The p.R45H variant (also known as c.134G>A), located in coding exon 2 of the SCN1B gene, results from a G to A substitution at nucleotide position 134. The arginine at codon 45 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.45	N
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.6	L;L;L;.;.;.
MutationTaster	Benign	0.69	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;.;D;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	D;.;D;.;.;.
Sift4G	Uncertain	0.039	D;.;D;T;.;.
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.30
MVP		0.96
MPC		1.7
ClinPred		0.36	T
GERP RS		2.8
Varity_R		0.43
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180943300; hg19: chr19-35523525; COSMIC: COSV52894541; COSMIC: COSV52894541;