19-35039139-C-G

Position:

• chr19-35039139-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000262631.11(SCN1B):​c.471C>G​(p.Ile157Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I157V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1B ENST00000262631.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.471C>G	p.Ile157Met	missense_variant	4/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_001321605.2	c.372C>G	p.Ile124Met	missense_variant	4/6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.471C>G	p.Ile157Met	missense_variant	4/6	1	NM_001037.5	ENSP00000262631	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Sep 30, 2023

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 157 of the SCN1B protein (p.Ile157Met). The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.4, and corresponds to NM_199037.3:c.*5041C>G in the primary transcript. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2024

The p.I157M variant (also known as c.471C>G), located in coding exon 4 of the SCN1B gene, results from a C to G substitution at nucleotide position 471. The isoleucine at codon 157 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D;.;.;.
Sift4G	Uncertain	0.017	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.57
MutPred		0.31		Gain of disorder (P = 0.0373);Gain of disorder (P = 0.0373);.;.;
MVP		0.96
ClinPred		0.75	D
GERP RS		1.8
Varity_R		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs765269835; hg19: chr19-35530043;