rs549232924

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001165963.4(SCN1A):c.2044-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,577,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.278

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-AS1 (HGNC:):

SCN1A-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 2-166042428-TA-T is Benign according to our data. Variant chr2-166042428-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 331892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166042428-TA-T is described in Lovd as [Benign]. Variant chr2-166042428-TA-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.2044-5delT		splice_region_variant, intron_variant		ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.2044-5delT	splice_region_variant, intron_variant		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 linkuse as main transcript	c.2044-5delT	splice_region_variant, intron_variant	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 linkuse as main transcript	c.2011-5delT	splice_region_variant, intron_variant	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 linkuse as main transcript	c.1960-5delT	splice_region_variant, intron_variant	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151106

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:

0.00316

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

223

AN:

1425878

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

106

AN XY:

709788

show subpopulations

Gnomad4 AFR exome

AF:

0.000215

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.000197

Gnomad4 EAS exome

AF:

0.000182

Gnomad4 SAS exome

AF:

0.0000826

Gnomad4 FIN exome

AF:

0.000251

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.0000680

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151218

Hom.:

Cov.:

AF XY:

0.0000677

AC XY:

AN XY:

73884

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:

0.0000886

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2021	Variant summary: SCN1A c.2044-5delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 228492 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is benign. c.2044-5delT has been reported in the literature in individuals affected with SCN1A-Related Seizure Disorder. This report does not provide unequivocal conclusions about association of the variant with SCN1A-Related Seizure Disorder (Ishii_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Familial hemiplegic migraine

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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