rs878854263

Positions:

• chr2-166002474-C-A
• chr2-166002474-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001165963.4(SCN1A):​c.4282G>T​(p.Val1428Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense, splice_region
• Scores: Splicing: ADA: 0.9926
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a intramembrane_region Pore-forming (size 21) in uniprot entity SCN1A_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• 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). GenCC has associacion of 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 2-166002474-C-A is Pathogenic according to our data. Variant chr2-166002474-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 238603.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4282G>T	p.Val1428Phe	missense_variant, splice_region_variant	24/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4282G>T	p.Val1428Phe	missense_variant, splice_region_variant	24/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4282G>T	p.Val1428Phe	missense_variant, splice_region_variant	23/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4249G>T	p.Val1417Phe	missense_variant, splice_region_variant	21/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4198G>T	p.Val1400Phe	missense_variant, splice_region_variant	21/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 16, 2016

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Val1428Ala) is reported in a patient with febrile seizures (PMID: 11524484), although the clinical significance of this variant is currently uncertain. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN1A-related disease. Family studies indicate this variant was not inherited from either parent (i.e. occurred de novo) in an individual with disease (Invitae database). This sequence change replaces valine with phenylalanine at codon 1428 of the SCN1A protein (p.Val1428Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In addition, algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing. These predictions have not been confirmed by published functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.8	.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;D;D;.;D;D;D;.
Vest4		0.92, 0.93, 0.93, 0.93
MutPred		0.76		.;.;Loss of ubiquitination at K1432 (P = 0.1388);.;.;Loss of ubiquitination at K1432 (P = 0.1388);.;.;.;
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
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: rs878854263; hg19: chr2-166858984;