rs104894718

Variant names:

• chr19-35033654-C-G
• rs104894718
• NM_001037.5:c.363C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-35033654-C-G
• chr19-35033654-C-A
• chr19-35033654-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PP3_Strong PP5_Very_Strong BS1_Supporting

The NM_001037.5(SCN1B):​c.363C>G​(p.Cys121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,076 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001786600: Functional studies in mice expressing the Scn1b-C121W (Scn1b+/W) allele compared to mice heterozygous for the Scn1b-null allele (Scn1b+/-) demonstrated the mice expressing the Scn1b+/W allele were more susceptible to hyperthermia-induced convulsions. The same study also demonstrated that the variant protein was expressed at lower levels in the brain (approximately 50% that of wild type) and may be incompletely glycosylated resulting in abnormal subcellular localization of the protein (Kruger et al. 2016)." and additional evidence is available in ClinVar. The gene SCN1B is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 1.99
• Publications: 52 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

Specifications for SCN1B are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786600: Functional studies in mice expressing the Scn1b-C121W (Scn1b+/W) allele compared to mice heterozygous for the Scn1b-null allele (Scn1b+/-) demonstrated the mice expressing the Scn1b+/W allele were more susceptible to hyperthermia-induced convulsions. The same study also demonstrated that the variant protein was expressed at lower levels in the brain (approximately 50% that of wild type) and may be incompletely glycosylated resulting in abnormal subcellular localization of the protein (Kruger et al. 2016).; SCV000223605: Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et al., 2013; Kruger et al., 2016); SCV000280460: "There is evidence that this variant leads to loss-of-function in terms of modulation of channel-gating kinetics (Wallace et al 1998; Tammaro et al 2002)."; SCV000768526: Experimental studies have shown that this missense change affects SCN1B function (PMID: 20628201, 25421039, 27277800, 28331474).; SCV003920421: "This variant is well characterized functionally, with in vitro studies demonstrating that this variant alters sodium channel activity, specifically temperature-dependent hyperexcitability (Selected publications: Wallace 1998 PMID: 9697698; Meadows 2002 PMID: 12486163; Tammaro 2002 PMID: 11866477; Egri 2012 PMID: 22292491)."; SCV000851613: In vitro and in vivo studies indicate that this alteration results in aberrant channel function, more specifically, thermal sensitive hyperexcitability (Barbieri, 2012; Meadows, 2002; Tammaro, 2002; Egri, 2012; Kruger, 2016; Baroni, 2013).; SCV004714492: "In vitro functional studies demonstrate a deleterious effect on SCN1B function by failing to modulate the sodium channel inactivating ability appropriately (Wallace et al. 1998. PubMed ID: 9697698) and in vivo functional studies demonstrates that mice expressing this variant were more prone to heat-induced seizures, decreased SCN1B protein expression in the brain, and subcellular mislocalization when compared to mice expressing wild type SCN1B (Kruger et al. 2016. PubMed ID: 27277800)."; SCV005900589: Functional studies including in vivo and in vitro studies have confirmed this variant leads to the disruption of the proper function of SCN1B protein (PMID: 22425777, 9697698, 12486163,19228957, 27277800).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 19-35033654-C-G is Pathogenic according to our data. Variant chr19-35033654-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000113 (165/1461892) while in subpopulation NFE AF = 0.000147 (164/1112012). AF 95% confidence interval is 0.000129. There are 0 homozygotes in GnomAdExome4. There are 88 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037.5. 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.363C>G	p.Cys121Trp	missense	Exon 3 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.363C>G	p.Cys121Trp	missense	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.264C>G	p.Cys88Trp	missense	Exon 3 of 6	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.363C>G	p.Cys121Trp	missense	Exon 3 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000415950.5	TSL:1	c.363C>G	p.Cys121Trp	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000638536.1	TSL:1	c.363C>G	p.Cys121Trp	missense	Exon 3 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 88 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000147 AC: 164 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Generalized epilepsy with febrile seizures plus, type 1 (5)
4	-	-	SCN1B-related disorder (4)
2	-	-	Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 (2)
1	-	-	Atrial fibrillation, familial, 13 (1)
1	-	-	Brugada syndrome 5 (1)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=3/97	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: rs104894718; hg19: chr19-35524558;