rs757649321

Positions:

• chr2-166013870-T-A
• chr2-166013870-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001165963.4(SCN1A):​c.3579A>T​(p.Gln1193His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0590

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)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ: 5.2206 (greater than the threshold 3.09). Trascript score misZ: 7.6022 (greater than threshold 3.09). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. GenCC has associacion of the gene with migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3579A>T	p.Gln1193His	missense_variant	21/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3579A>T	p.Gln1193His	missense_variant	21/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3579A>T	p.Gln1193His	missense_variant	20/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3546A>T	p.Gln1182His	missense_variant	18/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3495A>T	p.Gln1165His	missense_variant	18/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250794 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135584

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460240 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;.;.;D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	.;.;.;D;.;.;D;.;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.56	.;.;.;T;.;.;T;.;T;T
Polyphen		0.0070, 0.83	.;.;.;B;P;.;B;P;P;.
Vest4		0.60, 0.59, 0.61
MutPred		0.59		.;Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);.;.;Loss of sheet (P = 0.0457);.;.;.;
MVP		0.90
MPC		0.73
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.38
gMVP		0.75

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: rs757649321; hg19: chr2-166870380;