19-35039129-T-C

Position:

• chr19-35039129-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001037.5(SCN1B):​c.461T>C​(p.Met154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.33

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1297471).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.461T>C	p.Met154Thr	missense_variant	4/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_001321605.2	c.362T>C	p.Met121Thr	missense_variant	4/6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.461T>C	p.Met154Thr	missense_variant	4/6	1	NM_001037.5	ENSP00000262631	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN1B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 154 of the SCN1B protein (p.Met154Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. The SCN1B gene has multiple clinically relevant transcripts. The p.Met154Thr variant occurs in alternate transcript NM_001037.4, which corresponds to c.*5031T>C in NM_199037.3, the primary transcript listed in the Methods. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

SCN1B-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2024

The SCN1B c.461T>C variant is predicted to result in the amino acid substitution p.Met154Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.461T>C (p.M154T) alteration is located in exon 4 (coding exon 4) of the SCN1B gene. This alteration results from a T to C substitution at nucleotide position 461, causing the methionine (M) at amino acid position 154 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	.;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Benign	0.61	N;N;.;.
MutationTaster	Benign	0.56	D
PROVEAN	Benign	-1.3	N;.;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.34	T;.;.;.
Sift4G	Benign	0.35	T;.;T;.
Polyphen		0.010	B;B;B;.
Vest4		0.21
MutPred		0.33		Loss of catalytic residue at M154 (P = 0.0219);Loss of catalytic residue at M154 (P = 0.0219);.;.;
MVP		0.85
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.23

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: rs1432198305; hg19: chr19-35530033;