rs794726778

Positions:

• chr2-166043878-G-A
• chr2-166043878-G-C

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.1834C>T​(p.Arg612Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.58

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 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 2-166043878-G-A is Pathogenic according to our data. Variant chr2-166043878-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189941.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.1834C>T	p.Arg612Ter	stop_gained	14/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1834C>T	p.Arg612Ter	stop_gained	14/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.487+7748G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	The stop gained NM_001165963.4(SCN1A):c.1834C>T (p.Arg612Ter) has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 189941 as of 2021-07-01). The p.Arg612Ter variant is novel (not in any individuals) in gnomAD. The p.Arg612Ter 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 is a stop gained variant which occurs in an exon of SCN1A upstream of where nonsense mediated decay is predicted to occur. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 369 downstream pathogenic loss of function variants, with the furthest variant being 1314 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.Arg612Ter 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 503 others. This variant has been reported to be de novo in individuals affected with severe myoclonic epilepsy of infancy by Sun H et al., 2008. Loss-of-function variants in SCN1A are known to be pathogenic by Harkin L A et al., 2007. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 25, 2021	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189941). This premature translational stop signal has been observed in individual(s) with severe myoclonic epilepsy of infancy (PMID: 18554359). 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.Arg612*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.96, 0.97, 0.98, 0.97
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs794726778; hg19: chr2-166900388; COSMIC: COSV57662848;