rs67486287

chr19-35034040-G-Achr19-35034040-G-Cchr19-35034040-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000415950.5(SCN1B):c.749G>A(p.Arg250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,550,376 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.409

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056346953).
• BP6: Variant 19-35034040-G-A is Benign according to our data. Variant chr19-35034040-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35034040-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (35/152124) while in subpopulation SAS AF= 0.00355 (17/4786). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.448+301G>A		intron_variant		ENST00000262631.11
SCN1B	NM_199037.5	c.749G>A	p.Arg250Lys	missense_variant	3/3
SCN1B	NM_001321605.2	c.349+301G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+301G>A		intron_variant		1	NM_001037.5	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00355

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000795 AC: 123 AN: 154732 Hom.: 3 AF XY: 0.00121 AC XY: 99 AN XY: 81752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00509

Gnomad FIN exome AF: 0.000131

Gnomad NFE exome AF: 0.0000665

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000375 AC: 524 AN: 1398252 Hom.: 6 Cov.: 31 AF XY: 0.000526 AC XY: 363 AN XY: 689732

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00496

Gnomad4 FIN exome AF: 0.000304

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.000276

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74352

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00355

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000400 Hom.: 298

ExAC AF: 0.00128 AC: 51

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Brugada syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

SCN1B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	11
Dann	Benign	0.95
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.30	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.040	N;.
REVEL	Benign	0.066
Sift	Pathogenic	0.0	D;.
Polyphen		0.0010	B;.
Vest4		0.13
MVP		0.84
MPC		0.81
ClinPred		0.047	T
GERP RS		1.8
gMVP		0.22

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: rs67486287; hg19: chr19-35524944;