rs763254451

Positions:

• chr2-166015703-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001165963.4(SCN1A):​c.3454T>A​(p.Ser1152Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.32

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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). 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, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3454T>A	p.Ser1152Thr	missense_variant	20/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3454T>A	p.Ser1152Thr	missense_variant	20/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3454T>A	p.Ser1152Thr	missense_variant	19/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3421T>A	p.Ser1141Thr	missense_variant	17/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3370T>A	p.Ser1124Thr	missense_variant	17/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251062 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460708 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1152 of the SCN1A protein (p.Ser1152Thr). This variant is present in population databases (rs763254451, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 566881). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN1A protein function. 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. -

Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

The missense variant NM_001165963.4(SCN1A):c.3454T>A (p.Ser1152Thr) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser1152Thr variant is novel from South Asian background in gnomAD. The p.Ser1152Thr variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between serine and threonine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.22. The gene SCN1A contains 418 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Ser1152Thr missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 1152 of SCN1A is conserved in all mammalian species. The nucleotide c.3454 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. This variant was found in ClinVar (Variant 566881) with a classification of Uncertain Significance and a review status of (1 stars) criteria provided, single submitter. For these reasons, this variant has been classified as Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2019

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Predicted to be in the cytoplasmic loop between the second and third homologous domains -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.52	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	.;.;.;M;.;.;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.5	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.026	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.044	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.055	.;.;.;D;B;.;D;B;B;.
Vest4		0.56, 0.49, 0.48, 0.51
MutPred		0.49		.;Gain of glycosylation at S1151 (P = 0.0645);.;Gain of glycosylation at S1151 (P = 0.0645);.;.;Gain of glycosylation at S1151 (P = 0.0645);.;.;.;
MVP		0.96
MPC		1.3
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.54

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: rs763254451; hg19: chr2-166872213;