rs199727342

Positions:

• chr2-165992369-G-A
• chr2-165992369-G-T

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.4906C>T​(p.Arg1636*) 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 (★★).

• 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: 2.45

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165992369-G-A is Pathogenic according to our data. Variant chr2-165992369-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189870.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.4906C>T	p.Arg1636*	stop_gained	29/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4906C>T	p.Arg1636*	stop_gained	29/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4906C>T	p.Arg1636*	stop_gained	28/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4873C>T	p.Arg1625*	stop_gained	26/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4822C>T	p.Arg1608*	stop_gained	26/26	5		ENSP00000386312.1

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#: 189870; ClinVar); Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 374 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26467025, 21248271, 28202706, 21868258, 30034362, 32090326, 33278787, 31031587, 29655203, 34163418) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -

Severe myoclonic epilepsy in infancy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2012	- -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Arg1886*) have been determined to be pathogenic (PMID: 17054684, 18930999; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189870). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 21248271, 21868258, 28202706). 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 creates a premature translational stop signal (p.Arg1636*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 374 amino acid(s) of the SCN1A protein. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

The stop gained NM_001165963.4 (SCN1A):c.4906C>T (p.Arg1636Ter) has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 189870 as of 2021-11-04). The p.Arg1636Ter variant is novel (not in any individuals) in gnomAD. The p.Arg1636Ter variant is novel (not in any individuals) in 1kG. This variant is predicted to cause loss of normal protein function through protein truncation. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 66 downstream pathogenic loss of function variants, with the furthest variant being 297 residues downstream of this variant. This indicates that the region is critical to protein function. The gene SCN1A has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The p.Arg1636Ter variant is a loss of function variant in the gene SCN1A, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 513 others. The c.4906C>T variant in SCN1A is predicted conserved by GERP++ and PhyloP and damaging by CADD. This variant has previously been reported for focal epilepsy by Meng-Han Tsai et al., 2018. 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	0.62
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.96, 0.96, 0.97
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199727342; hg19: chr2-166848879; COSMIC: COSV100318750; COSMIC: COSV100318750;