rs192956852

chr2-166056520-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001165963.4(SCN1A):c.384-20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00668 in 1,509,564 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (60 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.242

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-166056520-C-G is Benign according to our data. Variant chr2-166056520-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 93648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166056520-C-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 931 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.384-20G>C		intron_variant		ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.384-20G>C		intron_variant			NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.488-18768C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 931 AN: 151956 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00733

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00617 AC: 1541 AN: 249896 Hom.: 15 AF XY: 0.00617 AC XY: 833 AN XY: 135030

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00668

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.00692

Gnomad OTH exome AF: 0.00872

GnomAD4 exome AF: 0.00674 AC: 9146 AN: 1357490 Hom.: 60 Cov.: 21 AF XY: 0.00661 AC XY: 4503 AN XY: 681718

Gnomad4 AFR exome AF: 0.000800

Gnomad4 AMR exome AF: 0.000899

Gnomad4 ASJ exome AF: 0.00826

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.00694

Gnomad4 OTH exome AF: 0.00536

GnomAD4 genome AF: 0.00612 AC: 931 AN: 152074 Hom.: 5 Cov.: 32 AF XY: 0.00704 AC XY: 523 AN XY: 74334

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00217

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.00733

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00635 Hom.: 0

Bravo AF: 0.00378

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2012	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2013	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SCN1A: BS1, BS2 -

SCN1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.4
Dann	Benign	0.66

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: rs192956852; hg19: chr2-166913030;