2-166056501-G-T

Variant names:

• chr2-166056501-G-T
• rs794726764
• NM_001165963.4:c.384-1C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001165963.4(SCN1A):​c.384-1C>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000702 in 1,424,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014925373 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.384-1C>A		splice_acceptor_variant, intron_variant	Intron 5 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.384-1C>A		splice_acceptor_variant, intron_variant	Intron 5 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.384-1C>A		splice_acceptor_variant, intron_variant	Intron 4 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.384-1C>A		splice_acceptor_variant, intron_variant	Intron 2 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.384-1C>A		splice_acceptor_variant, intron_variant	Intron 4 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424510 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 711242

African (AFR) AF: 0.00 AC: 0 AN: 32634

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078302

Other (OTH) AF: 0.00 AC: 0 AN: 59132

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.0	.;.;.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.
PhyloP100		6.0
PROVEAN	Benign	0.0	.;.;.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.
Vest4		0.0
GERP RS		5.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794726764; hg19: chr2-166913011;