2-166073552-C-T

Position:

• chr2-166073552-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_001165963.4(SCN1A):​c.70G>A​(p.Ala24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.77

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 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 127) in uniprot entity SCN1A_HUMAN there are 76 pathogenic changes around while only 9 benign (89%) 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.
• PP5: Variant 2-166073552-C-T is Pathogenic according to our data. Variant chr2-166073552-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190023.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.70G>A	p.Ala24Thr	missense_variant	4/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.70G>A	p.Ala24Thr	missense_variant	4/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.488-1736C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Bioinformatics, Peking University

Dec 20, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T;T;T;T;.;T;.;.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	.;.;.;M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	.;.;.;N;.;.;N;.;N;N
REVEL	Pathogenic	0.87
Sift	Benign	0.039	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.28	.;.;.;T;.;.;T;.;T;T
Polyphen		0.41	.;.;.;.;B;.;.;B;B;.
Vest4		0.36, 0.75, 0.61, 0.62
MutPred		0.41		Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);Gain of phosphorylation at A24 (P = 0.0194);
MVP		0.98
MPC		0.66
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.16
gMVP		0.60

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: rs794726848; hg19: chr2-166930062;