rs369588692

chr19-35033964-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000415950.5(SCN1B):c.673C>T(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,552,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. R225H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (1 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.378

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03603211).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000657 (92/1400142) while in subpopulation MID AF= 0.000702 (4/5698). AF 95% confidence interval is 0.000239. There are 1 homozygotes in gnomad4_exome. There are 54 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.448+225C>T		intron_variant		ENST00000262631.11
SCN1B	NM_199037.5	c.673C>T	p.Arg225Cys	missense_variant	3/3
SCN1B	NM_001321605.2	c.349+225C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+225C>T		intron_variant		1	NM_001037.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000122 AC: 19 AN: 156104 Hom.: 0 AF XY: 0.000109 AC XY: 9 AN XY: 82454

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 92 AN: 1400142 Hom.: 1 Cov.: 33 AF XY: 0.0000782 AC XY: 54 AN XY: 690716

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000239

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000491

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000227 AC: 1

ExAC AF: 0.0000615 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2017

A variant of uncertain significance has been identified in an alternative transcript of the SCN1B gene. The R225C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R225C variant is observed in 2/8002 (0.02%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R225C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Brugada syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the SCN1B protein (p.Arg225Cys). This variant is present in population databases (rs369588692, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 28074886, 29915715). ClinVar contains an entry for this variant (Variation ID: 242250). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN1B function (PMID: 29915715). 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
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.59
Dann	Benign	0.52
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.48	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.029	D;.
Polyphen		0.0	B;.
Vest4		0.093
MVP		0.20
MPC		0.91
ClinPred		0.079	T
GERP RS		-6.8
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369588692; hg19: chr19-35524868;