2-166012170-G-A

Position:

• chr2-166012170-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.3818C>T​(p.Ala1273Val) variant causes a missense 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 13) in uniprot entity SCN1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• 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, 0.949
• PP5: Variant 2-166012170-G-A is Pathogenic according to our data. Variant chr2-166012170-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3818C>T	p.Ala1273Val	missense_variant	22/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3818C>T	p.Ala1273Val	missense_variant	22/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3818C>T	p.Ala1273Val	missense_variant	21/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3785C>T	p.Ala1262Val	missense_variant	19/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3734C>T	p.Ala1245Val	missense_variant	19/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2016

The A1273V variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1273V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (K1270T, Y1274N, Y1274S, G1275A, G1275V) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A1273V variant is a strong candidate for a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.0090	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.66	.;.;.;D;P;.;D;P;P;.
Vest4		0.95, 0.99, 0.99, 0.98
MutPred		0.77		.;Gain of methylation at K1270 (P = 0.1195);.;Gain of methylation at K1270 (P = 0.1195);.;.;Gain of methylation at K1270 (P = 0.1195);.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs794726841; hg19: chr2-166868680;