rs77216276

Positions:

chr2-165991541-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001165963.4(SCN1A):c.5734C>T(p.Arg1912*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,128 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SCN1A
NM_001165963.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.891

Variant links:

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 links:

SCN1A (HGNC:):

SCN1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-165991541-G-A is Pathogenic according to our data. Variant chr2-165991541-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 496124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165991541-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.5734C>T	p.Arg1912*	stop_gained	29/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.5734C>T	p.Arg1912*	stop_gained	29/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 linkuse as main transcript	c.5734C>T	p.Arg1912*	stop_gained	28/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 linkuse as main transcript	c.5701C>T	p.Arg1901*	stop_gained	26/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 linkuse as main transcript	c.5650C>T	p.Arg1884*	stop_gained	26/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250832

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2021	Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 98 amino acids are lost, and other loss-of-function variants have been reported downstream in the published literature; Lost residues are located within the C-terminal cytoplasmic domain and IQ domain; This variant is associated with the following publications: (PMID: 23195492, 21844054, 22344438, 14738421, 31009440, 30868114, 31864146, 32090326, 32540801, 31035242, 20522430) -

Autosomal dominant epilepsy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 03, 2016

Variant summary: SCN1A c.5734C>T variant results in a premature termination codon, predicted to cause a truncated or absent SCN1A protein, which is a commonly known mechanism for SCN1A-related seizure disorders. Mutation Taster predicts a damaging outcome for this variant, but functional studies have not been carried out to confirm this prediction. This variant is found in 1/121470 control chromosomes at a frequency of 0.0000082, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0000179). However, the variant has been identified in multiple affected patients in the literature as a de novo mutation, and also as a paternally inherited variant from an asymptomatic mosaic father. Taken together, this is a disease variant and was classified as pathogenic. -

Migraine, familial hemiplegic, 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Apr 10, 2022

The c.5734C>T;p.(Arg1912*) variant creates a premature translational stop signal in the SCN1A gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD) type change; it is present in a relevant exon to the transcript, and disrupts >10% of the protein product. PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 496124 ; PMID: 14738421; 20522430; 21844054; 30868114) - PS4. The variant is present at low allele frequencies population databases (rs77216276 – gnomAD 0.0006579%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 21844054; 30868114) - 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

Sep 10, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496124). This variant is also known as R1902X. This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 14738421, 20522430, 23195492; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs77216276, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1912*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the SCN1A protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

Vest4

0.95, 0.95, 0.96

GERP RS

1.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over