chr2-165996021-G-A

Position:

• chr2-165996021-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.4573C>T​(p.Arg1525Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.78

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165996021-G-A is Pathogenic according to our data. Variant chr2-165996021-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996021-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4573C>T	p.Arg1525Ter	stop_gained	27/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-19592G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4573C>T	p.Arg1525Ter	stop_gained	27/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-19592G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2023	This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2016	The Arg1525Stop variant in the SCN1A gene has been reported in several individuals with SCN1A-related disorders (Kearney et al., 2006; Harkin et al., 2007). This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. This variant has been seen apparently mosaic. -

Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Apr 10, 2022

The c.4573C>T;p.(Arg1525*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 189911; PMID: 28079314; 27465585; 17347258; 16458823) - PS4. This variant is not present in population databases (rs794726752- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27465585) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

This sequence change creates a premature translational stop signal (p.Arg1525*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 16458823, 27465585, 28079314). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Bioinformatics, Peking University

Dec 20, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.96, 0.96
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726752; hg19: chr2-166852531; COSMIC: COSV57669725; COSMIC: COSV57669725;