rs794726768

Variant names:

• chr2-166047749-T-A
• rs794726768
• NM_001165963.4:c.1048A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166047749-T-A
• chr2-166047749-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353961.2(SCN1A):​c.-1378A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001353961.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.360

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08861196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1048A>T	p.Met350Leu	missense_variant	Exon 11 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1048A>T	p.Met350Leu	missense_variant	Exon 11 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1048A>T	p.Met350Leu	missense_variant	Exon 10 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1048A>T	p.Met350Leu	missense_variant	Exon 8 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1048A>T	p.Met350Leu	missense_variant	Exon 8 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.36
DEOGEN2	Uncertain	0.63	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.20	T;T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.28	.;.;.;N;N;.;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.28	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.18	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.67	.;.;.;T;.;.;T;.;T;T
Polyphen		0.0, 0.0010	.;.;.;B;B;.;B;B;B;.
Vest4		0.44, 0.45, 0.45, 0.44
MutPred		0.48		Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);Loss of ubiquitination at K353 (P = 0.0853);
MVP		0.86
MPC		0.63
ClinPred		0.22	T
GERP RS		-1.9
Varity_R		0.084
gMVP		0.88

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: rs794726768; hg19: chr2-166904259;