rs267607028

Variant names:

• chr19-35033827-G-A
• rs267607028
• ENST00000415950.5:c.536G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Strong PS3 PP5

The NM_199037.5(SCN1B):​c.536G>A​(p.Trp179*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000959398: Experimental studies have shown that this premature translational stop signal affects SCN1B function (PMID:18464934).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SCN1B NM_199037.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.35
• Publications: 4 publications found

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]

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000959398: Experimental studies have shown that this premature translational stop signal affects SCN1B function (PMID: 18464934).
• PP5: Variant 19-35033827-G-A is Pathogenic according to our data. Variant chr19-35033827-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9254.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199037.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.448+88G>A		intron	N/A	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.536G>A	p.Trp179*	stop_gained	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.349+88G>A		intron	N/A	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000415950.5	TSL:1	c.536G>A	p.Trp179*	stop_gained	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+88G>A		intron	N/A	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000638536.1	TSL:1	c.448+88G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248926 AF XY: 0.00000741

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460468 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111580

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000502 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Brugada syndrome 5 (2)
-	1	-	Atrial fibrillation, familial, 13 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		2.3
Vest4		0.46
GERP RS		2.5
Mutation Taster		=56/144	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607028; hg19: chr19-35524731;