19-35030828-G-T

Position:

• chr19-35030828-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001037.5(SCN1B):​c.8G>T​(p.Arg3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 938,412 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0240

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2290327).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.8G>T	p.Arg3Met	missense_variant	1/6	ENST00000262631.11
SCN1B	NM_199037.5	c.8G>T	p.Arg3Met	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.8G>T	p.Arg3Met	missense_variant	1/6	1	NM_001037.5	P1
SCN1B	ENST00000415950.5	c.8G>T	p.Arg3Met	missense_variant	1/3	1
SCN1B	ENST00000638536.1	c.8G>T	p.Arg3Met	missense_variant	1/5	1		P1
SCN1B	ENST00000595652.5	c.8G>T	p.Arg3Met	missense_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000746 AC: 7 AN: 938412 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 457982

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000880

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 3 of the SCN1B protein (p.Arg3Met). 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: 1302666). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Apr 11, 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 -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The p.R3M variant (also known as c.8G>T), located in coding exon 1 of the SCN1B gene, results from a G to T substitution at nucleotide position 8. The arginine at codon 3 is replaced by methionine, an amino acid with 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	0.21
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.055	T;T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.35	.;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.46	N;.;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.11	T;.;D;.
Sift4G	Benign	0.10	T;.;T;T
Polyphen		0.70	P;P;P;B
Vest4		0.21
MutPred		0.35		Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);
MVP		0.84
MPC		0.75
ClinPred		0.067	T
GERP RS		0.0044
Varity_R		0.054
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35521732;