2-166056412-C-G

Variant names:

• chr2-166056412-C-G
• rs796053090
• NM_001165963.4:c.472G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001165963.4(SCN1A):​c.472G>C​(p.Glu158Gln) 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. 13/23 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense, splice_region
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.82

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 24) in uniprot entity SCN1A_HUMAN there are 5 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 the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-166056412-C-G is Pathogenic according to our data. Variant chr2-166056412-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206928.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.472G>C	p.Glu158Gln	missense_variant, splice_region_variant	Exon 6 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.472G>C	p.Glu158Gln	missense_variant, splice_region_variant	Exon 6 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.472G>C	p.Glu158Gln	missense_variant, splice_region_variant	Exon 5 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.472G>C	p.Glu158Gln	missense_variant, splice_region_variant	Exon 3 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.472G>C	p.Glu158Gln	missense_variant, splice_region_variant	Exon 3 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jan 09, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in a patient with epilepsy in published literature (PMID: 29655203); This substitution is predicted to be within the transmembrane segment S2 of the first homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 37955180) -

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe myoclonic epilepsy in infancy Pathogenic:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Sep 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 158 of the SCN1A protein (p.Glu158Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206928). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant identified in the SCN1A gene is located in the transmembrane spanning D1-S2 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.032	.;.;.;D;.;.;D;.;D;D
Polyphen		0.99, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.87, 0.83, 0.84, 0.89
MutPred		0.80		Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);Loss of ubiquitination at K155 (P = 0.0755);
MVP		1.0
MPC		0.83
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.90
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: rs796053090; hg19: chr2-166912922;