rs794726746

Variant names:

• chr2-166036492-A-C
• rs794726746
• NM_001165963.4:c.2985T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001165963.4(SCN1A):​c.2985T>G​(p.Phe995Leu) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.60

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat II (size 272) in uniprot entity SCN1A_HUMAN there are 49 pathogenic changes around while only 2 benign (96%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.87
• PP5: Variant 2-166036492-A-C is Pathogenic according to our data. Variant chr2-166036492-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 189905.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2985T>G	p.Phe995Leu	missense_variant	Exon 19 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2985T>G	p.Phe995Leu	missense_variant	Exon 19 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2985T>G	p.Phe995Leu	missense_variant	Exon 18 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2952T>G	p.Phe984Leu	missense_variant	Exon 16 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2901T>G	p.Phe967Leu	missense_variant	Exon 16 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

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

- -

not provided Uncertain:1

Jun 05, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe995Leu (TTT>TTG): c.2985 T>G in exon 16 of the SCN1A gene (NM_001165963.1) The F995L missense variant has been reported in association with Dravet syndrome in an external mutation database; however no information about the variant was available in the publication. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a conserved position in the cytoplasmic loop between the second and third homologous domains, and several other missense mutations (L990F, S993R, D998G) have been reported in this region of the protein in association with epilepsy. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, it is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	.;.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.0070	.;.;.;D;.;.;D;.;D;D
Polyphen		0.94, 0.015	.;.;.;P;B;.;P;B;B;.
Vest4		0.84, 0.90, 0.84, 0.83
MutPred		0.50		.;Loss of catalytic residue at F995 (P = 0.0476);.;Loss of catalytic residue at F995 (P = 0.0476);.;.;Loss of catalytic residue at F995 (P = 0.0476);.;.;.;
MVP		1.0
MPC		2.8
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.88
gMVP		0.96

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: rs794726746; hg19: chr2-166893002;