rs794726803

chr2-166058569-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):c.383+1A>G variant causes a splice donor 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 splice_donor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02

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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.019568823 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 45, new splice context is: tctGTaagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.417
• PP5: Variant 2-166058569-T-C is Pathogenic according to our data. Variant chr2-166058569-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 189967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.383+1A>G		splice_donor_variant		ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.383+1A>G		splice_donor_variant			NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.488-16719T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2017

The c.383+1A>G intronic pathogenic mutation results from an A to G substitution one nucleotide after coding exon 2 of the SCN1A gene. This mutation has been detected as de novo occurrences in two unrelated individuals fulfilling diagnostic criteria for Dravet syndrome and Lennox-Gastaut syndrome (LGS); however paternity was not confirmed in either case (Selmer KK, et al. Epilepsy Behav 2009; 16(3):555-7. Xu X, et al. Brain Dev. 2014; 36(8):676-81). A similar alteration, located at the same nucleotide position, c.383+1A>C, was detected in an individual fulfilling diagnostic criteria for Dravet syndrome (Depienne C, et al. J. Med. Genet. 2009; 46(3):183-91). Based on the supporting evidence, c.383+1A>G is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2020

For these reasons, this variant has been classified as Pathogenic. A different variant affecting this nucleotide (c.383+1A>C) has been determined to be pathogenic (PMID: 18930999). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. This variant has been observed in individuals affected with early infantile epileptic encephalopathy or Dravet syndrome, in some of whom it was found de novo (PMID: 23884151, 19782004, Invitae). ClinVar contains an entry for this variant (Variation ID: 189967). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 2 of the SCN1A gene. It does not directly change the encoded amino acid sequence of the SCN1A protein, but it affects a nucleotide within the consensus splice site of the intron. -

Severe myoclonic epilepsy in infancy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Bioinformatics, Peking University

Dec 20, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs794726803; hg19: chr2-166915079; COSMIC: COSV57668946;