rs1553521567

Variant names:

• chr2-165996118-G-A
• rs1553521567
• NM_001165963.4:c.4477-1C>T

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.4477-1C>T variant causes a splice acceptor, 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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)

LOC102724058 (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 0.017412934 fraction of the gene. Cryptic splice site detected, with MaxEntScore 1.1, offset of 28, new splice context is: tcaagacatctttatgacAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165996118-G-A is Pathogenic according to our data. Variant chr2-165996118-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 530456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4477-1C>T		splice_acceptor_variant, intron_variant	Intron 26 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4477-1C>T		splice_acceptor_variant, intron_variant	Intron 26 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4477-1C>T		splice_acceptor_variant, intron_variant	Intron 25 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4444-1C>T		splice_acceptor_variant, intron_variant	Intron 23 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4393-1C>T		splice_acceptor_variant, intron_variant	Intron 23 of 25	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 530456). Disruption of this splice site has been observed in individual(s) with infantile onset myoclonic epilepsy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 23 of the SCN1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 23 of the SCN1A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported to be de novo in an individuals affected with infantile onset myoclonic epilepsy. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle, D et al), and loss-of-function variants in SCN1A are known to be pathogenic (Depienne C et al, Harkin LA et al). The variant is reported in ClinVar as pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and in gnomAD. The nucleotide change in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553521567; hg19: chr2-166852628;