rs121434627

chr19-35033550-G-Achr19-35033550-G-Cchr19-35033550-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001037.5(SCN1B):c.259G>A(p.Glu87Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. E87Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.986

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001037.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.16314626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.259G>A	p.Glu87Lys	missense_variant	3/6	ENST00000262631.11
SCN1B	NM_199037.5	c.259G>A	p.Glu87Lys	missense_variant	3/3
SCN1B	NM_001321605.2	c.160G>A	p.Glu54Lys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.259G>A	p.Glu87Lys	missense_variant	3/6	1	NM_001037.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251356 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461822 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74304

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2020

This sequence change replaces glutamic acid with lysine at codon 87 of the SCN1B protein (p.Glu87Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121434627, ExAC 0.006%). This variant has not been reported in the literature in individuals with SCN1B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T;T;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.21	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	0.58	N;N;N;.;.
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.52	N;.;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.72	T;.;T;.;.
Sift4G	Benign	0.92	T;.;T;.;.
Polyphen		0.90	P;P;D;.;.
Vest4		0.35
MutPred		0.55		Gain of methylation at E87 (P = 0.005);Gain of methylation at E87 (P = 0.005);Gain of methylation at E87 (P = 0.005);.;.;
MVP		0.97
MPC		1.1
ClinPred		0.17	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.92

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: rs121434627; hg19: chr19-35524454;