rs794726849

Variant names:

• chr2-166056451-T-C
• rs794726849
• NM_001165963.4:c.433A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001353961.2(SCN1A):​c.-1993A>G variant causes a 5 prime UTR premature start codon gain 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001353961.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.93

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 2-166056451-T-C is Pathogenic according to our data. Variant chr2-166056451-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 190024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.433A>G	p.Met145Val	missense_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.433A>G	p.Met145Val	missense_variant	Exon 6 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.433A>G	p.Met145Val	missense_variant	Exon 5 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.433A>G	p.Met145Val	missense_variant	Exon 3 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.433A>G	p.Met145Val	missense_variant	Exon 3 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	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	-3.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;.;D;.;D;D
Polyphen		0.92, 0.98	.;.;.;P;D;.;P;D;D;.
Vest4		0.87, 0.91, 0.85, 0.89
MutPred		0.56		Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);
MVP		0.99
MPC		0.69
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.79
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs794726849; hg19: chr2-166912961;