2-165991641-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_001165963.4(SCN1A):c.5634G>C(p.Glu1878Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1878N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.121

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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001165963.4
• PP2: Missense variant where missense usually causes diseases, SCN1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.30592793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5634G>C	p.Glu1878Asp	missense_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-23972C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5634G>C	p.Glu1878Asp	missense_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-23972C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250504 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135334

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727178

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2020

The p.E1878D variant (also known as c.5634G>C), located in coding exon 26 of the SCN1A gene, results from a G to C substitution at nucleotide position 5634. The glutamic acid at codon 1878 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported as inherited from an unaffected mother on whole exome findings for a PIGN-related epilepsy case with several additional variants also reported (Fleming L et al. Am. J. Med. Genet. A, 2016 Jan;170A:77-86). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

A heterozygous missense variant was identified, NM_006920.4(SCN1A):c.5601G>C in exon 26 of 26 of the SCN1A gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to an aspartic aicd at position 1867 of the protein; NP_008851.3(SCN1A):p.(Glu1867Asp). The glutamic acid at this position has high conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0008% (2 heterozygotes). Several alternative residue changes at the same location has been reported in the gnomAD database at a highest frequency of 0.005%. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2023

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. 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 not expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 940921). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1878 of the SCN1A protein (p.Glu1878Asp). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	17
Dann	Benign	0.93
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T;T;T;.;.;.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.70	T
Polyphen		0.12	.;.;.;.;B;.;B;B;.
Vest4		0.16, 0.17, 0.17, 0.30
MutPred		0.29		.;.;.;Loss of ubiquitination at K1873 (P = 0.1083);.;Loss of ubiquitination at K1873 (P = 0.1083);.;.;.;
MVP		0.96
MPC		0.71
ClinPred		0.19	T
GERP RS		0.41
Varity_R		0.13
gMVP		0.72

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: rs748090629; hg19: chr2-166848151;