2-165991892-C-T

Position:

• chr2-165991892-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001165963.4(SCN1A):​c.5383G>A​(p.Glu1795Lys) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 7.85

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat IV (size 298) in uniprot entity SCN1A_HUMAN there are 62 pathogenic changes around while only 3 benign (95%) 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, 0.868
• PP5: Variant 2-165991892-C-T is Pathogenic according to our data. Variant chr2-165991892-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68660.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.5383G>A	p.Glu1795Lys	missense_variant	29/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5383G>A	p.Glu1795Lys	missense_variant	29/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5383G>A	p.Glu1795Lys	missense_variant	28/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5350G>A	p.Glu1784Lys	missense_variant	26/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.5299G>A	p.Glu1767Lys	missense_variant	26/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1795 of the SCN1A protein (p.Glu1795Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of generalized epilepsy with febrile seizures plus (GEFS+) (PMID: 20600615; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68660). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2017

A variant of uncertain significance has been identified in the SCN1A gene. The E1795K variant has been previously reported in multiple affected individuals in a family with generalized epilepsy with febrile seizures plus (GEFS+) (Li et al., 2010). The E1795K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E1795K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain, and missense variants in this region have been reported in association with SCN1A-related disorders (SCN1A Variant Database; Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Generalized epilepsy with febrile seizures plus, type 1 Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;M;.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Sift4G	Benign	0.095	.;.;.;T;.;T;.;T;T
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.82, 0.90, 0.88, 0.85
MutPred		0.33		.;.;.;Gain of ubiquitination at E1795 (P = 0.0031);.;Gain of ubiquitination at E1795 (P = 0.0031);.;.;.;
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.96

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: rs121918813; hg19: chr2-166848402; COSMIC: COSV57663562; COSMIC: COSV57663562;