rs931949929

Positions:

• chr19-35033607-A-G
• chr19-35033607-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_001037.5(SCN1B):​c.316A>G​(p.Ile106Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I106F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.61

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 disulfide_bond (size 81) in uniprot entity SCN1B_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_001037.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35033607-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 375687.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.316A>G	p.Ile106Val	missense_variant	3/6	ENST00000262631.11
SCN1B	NM_199037.5	c.316A>G	p.Ile106Val	missense_variant	3/3
SCN1B	NM_001321605.2	c.217A>G	p.Ile73Val	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.316A>G	p.Ile106Val	missense_variant	3/6	1	NM_001037.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 23, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 106 of the SCN1B protein (p.Ile106Val). This variant is not present in population databases (gnomAD no frequency). 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: 1706108). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The p.I106V variant (also known as c.316A>G), located in coding exon 3 of the SCN1B gene, results from an A to G substitution at nucleotide position 316. The isoleucine at codon 106 is replaced by valine, 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	Benign	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.6	L;L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.70	N;.;N;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.15	T;.;T;.;.
Sift4G	Benign	0.19	T;.;T;.;.
Polyphen		0.90	P;P;D;.;.
Vest4		0.35
MVP		0.98
MPC		0.97
ClinPred		0.58	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.88

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: rs931949929; hg19: chr19-35524511;