rs199685662

Positions:

• chr19-35033779-G-A

Variant summary

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

The NM_199037.5(SCN1B):​c.488G>A​(p.Arg163Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SCN1B NM_199037.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -1.19

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=0.039584577).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0002 (293/1461472) while in subpopulation NFE AF= 0.000242 (269/1112008). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4_exome. There are 141 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 GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+40G>A		intron_variant		ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.488G>A	p.Arg163Gln	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2	c.349+40G>A		intron_variant			NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+40G>A		intron_variant		1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250606 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135600

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000200 AC: 293 AN: 1461472 Hom.: 0 Cov.: 33 AF XY: 0.000194 AC XY: 141 AN XY: 727048

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000242

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74436

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000233 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2024	Reported in two siblings with a history of intractable epilepsy, hypotonia, global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features; however, the variant was inherited from an unaffected father and additional compound heterozygous variants in the PIGN gene were identified that were expected to explain the familial phenotype (PMID: 26394714); In silico analysis indicates that this missense variant does not alter protein structure/function; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 26394714) -

Brugada syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 163 of the SCN1B protein (p.Arg163Gln). This variant is present in population databases (rs199685662, gnomAD 0.02%). 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: 406499). 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	-0.37	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.61
DANN	Benign	0.89
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.48	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.76	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.34	N;.
REVEL	Benign	0.13
Sift	Benign	0.35	T;.
Sift4G	Benign	0.36	T;.
Polyphen		0.029	B;.
Vest4		0.069
MVP		0.48
MPC		0.81
ClinPred		0.017	T
GERP RS		-6.2
gMVP		0.47

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: rs199685662; hg19: chr19-35524683;