rs121917990

Variant names:

• chr2-166043836-T-A
• rs121917990
• NM_001165963.4:c.1876A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166043836-T-A
• chr2-166043836-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001353961.2(SCN1A):​c.-550A>T variant causes a 5 prime UTR premature start codon gain change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001353961.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1876A>T	p.Ser626Cys	missense_variant	Exon 14 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1876A>T	p.Ser626Cys	missense_variant	Exon 14 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1876A>T	p.Ser626Cys	missense_variant	Exon 13 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1876A>T	p.Ser626Cys	missense_variant	Exon 11 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1876A>T	p.Ser626Cys	missense_variant	Exon 11 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 19, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S626C variant (also known as c.1876A>T), located in coding exon 11 of the SCN1A gene, results from an A to T substitution at nucleotide position 1876. The serine at codon 626 is replaced by cysteine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;M;.;M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.012	.;.;.;D;.;.;D;.;D;D
Polyphen		0.0080, 1.0	.;.;.;B;D;.;B;D;D;.
Vest4		0.77, 0.82, 0.82, 0.81
MutPred		0.28		.;Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);Loss of phosphorylation at S626 (P = 0.0457);
MVP		0.95
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.81

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: rs121917990; hg19: chr2-166900346;