rs398123595

Positions:

• chr2-166002470-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.4284+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9898
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04660033 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166002470-A-G is Pathogenic according to our data. Variant chr2-166002470-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 93651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4284+2T>C		splice_donor_variant, intron_variant		ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4284+2T>C		splice_donor_variant, intron_variant			NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4284+2T>C		splice_donor_variant, intron_variant		5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4251+2T>C		splice_donor_variant, intron_variant		5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4200+2T>C		splice_donor_variant, intron_variant		5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	The c.4284+2 T>C splice site variant in the SCN1A gene has been previously reported in association with Dravet syndrome (Wang et al., 2012; Xiong et al., 2016). This pathogenic variant destroys the canonical splice donor site in intron 21, and is expected to cause abnormal gene splicing. This variant is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the third homologous domain. Additionally, the c.4284+2 T>C variant is not observed in large population cohorts (Lek et al., 2016). Furthermore, nearby splice site variants in this intron have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorders (Stenson et al., 2014). Therefore, the presence of this variant is consistent with the diagnosis of an SCN1A-related disorder in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 50
DS_DL_spliceai		0.93		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123595; hg19: chr2-166858980; COSMIC: COSV57684938; COSMIC: COSV57684938;