2-166042428-TA-TAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001165963.4(SCN1A):c.2044-5_2044-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,580,304 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: SCN1A NM_001165963.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.278

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-166042428-T-TA is Benign according to our data. Variant chr2-166042428-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194032.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2044-5_2044-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2044-5_2044-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+6307dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000311 AC: 47 AN: 151114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000631 AC: 902 AN: 1429078 Hom.: 6 Cov.: 31 AF XY: 0.000756 AC XY: 538 AN XY: 711340

Gnomad4 AFR exome AF: 0.000428

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.0000785

Gnomad4 EAS exome AF: 0.000389

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.000154

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.000593

GnomAD4 genome AF: 0.000311 AC: 47 AN: 151226 Hom.: 1 Cov.: 33 AF XY: 0.000271 AC XY: 20 AN XY: 73892

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.00417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SCN1A: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2014

The variant is found in INFANT-EPI panel(s). -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs549232924; hg19: chr2-166898938;