2-166054637-C-T

Position:

• chr2-166054637-C-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.602+1G>A 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. 3/3 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 U:1
• Conservation: PhyloP100: 7.90

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021227198 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 2-166054637-C-T is Pathogenic according to our data. Variant chr2-166054637-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 197187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166054637-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.602+1G>A		splice_donor_variant		ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.602+1G>A		splice_donor_variant			NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.487+18507C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2017	The c.602+1 G>A splice site variant in the SCN1A gene has been reported previously multiple times as an assumed de novo or an inherited variant in association with Dravet syndrome and other SCN1A-related disorders (Fujiwara et al., 2003; Harkin et al., 2007; Depienne et al., 2009; SCN1A Variant Database). It has also been observed as an assumed de novo variant in individuals with epilepsy tested previously at GeneDx. The c.602+1 G>A pathogenic variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. It is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.602+1 G>A is consistent with the diagnosis of a SCN1A-related disorder in this individual. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	SCN1A: PVS1, PM2 -

Severe myoclonic epilepsy in infancy Pathogenic:3 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 18, 2017	The observed variant c.602+1G>A (5' splice site) has not been reported in 1000 genomes and ExAC databases. However, it is reported in a publication by Djemie T et al. 2016. The in silico prediction of the variant is damaging by MutationTaster2. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Aug 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. The variant on the canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000197187/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 25, 2021	- -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jul 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 18, 2023	- -

Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

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Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 22, 2023

Disruption of this splice site has been observed in individual(s) with Dravet syndrome and SCN1A-related disease (PMID: 12566275, 20522430, 23934111, 28148630). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 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). This variant is also known as exon 4 splice site GT>AT, and 2:166911147 C/T. 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: 197187). -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Dec 08, 2021

SCN1A NM_001165963.1 exon 4 c.602+1G>A: This variant has been reported in the literature in at least 8 individuals with Dravet syndrome/epileptic encephalopathy, segregating with disease in at least 2 affected family members and reported as de novo in at least 4 individuals (Marini 2006 PMID:17054697, Depienne 2010 PMID:20522430, Rodda 2012 PMID:22409937, Allen 2013 PMID:23934111, Ortega-Moreno 2017 PMID:29190809, Turner 2017 PMID:28148630). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:197187). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function has been reported as a disease mechanism for this gene and disease (Depienne 2009 PMID:18930999). In summary, this variant is classified as pathogenic. -

Developmental and epileptic encephalopathy, 76 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The c.602+1 G>A splice site variant in the SCN1A gene has been reported previously in heterozygous state in several individuals affected with SCN1A-related disease (Fujiwara et al.,2003; Epi4K Consortium. et al., 2013) and observed to segregate with Dravet syndrome in a family (Depienne et al., 2009). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic. The nucleotide change in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change affects a donor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle et al., 2005), and loss-of-function variants in SCN1A are known to be pathogenic (Harkin et al., 2007). For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 03, 2018

SCN1A NM_001165963.1 exon 4 c.602+1G>A: This variant has been reported in the literature in at least 8 individuals with Dravet syndrome/epileptic encephalopathy, segregating with disease in at least 2 affected family members and reported as de novo in at least 4 individuals (Marini 2006 PMID:17054697, Depienne 2010 PMID:20522430, Rodda 2012 PMID:22409937, Allen 2013 PMID:23934111, Ortega-Moreno 2017 PMID:29190809, Turner 2017 PMID:28148630). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:197187). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function has been reported as a disease mechanism for this gene and disease (Depienne 2009 PMID:18930999). In summary, this variant is classified as pathogenic. -

Focal impaired awareness seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pediatrics, MediClubGeorgia

Nov 01, 2020

This sequence change affects a donor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function. Unaffected mother is mosaic for this variant. This variant has been described in several affected individuals. -

Autism;C0036572:Seizure;C0557874:Global developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs794726827; hg19: chr2-166911147; COSMIC: COSV57662425;