rs1057519529

Positions:

• chr2-166043864-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PS1_Moderate PM2 PP2 PP5_Moderate BP4

The NM_001165963.4(SCN1A):​c.1848G>C​(p.Glu616Asp) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.222

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_001165963.4 (SCN1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 2-166043864-C-G is Pathogenic according to our data. Variant chr2-166043864-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 375511.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27450728). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1848G>C	p.Glu616Asp	missense_variant	14/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1848G>C	p.Glu616Asp	missense_variant	14/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1848G>C	p.Glu616Asp	missense_variant	13/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1848G>C	p.Glu616Asp	missense_variant	11/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1848G>C	p.Glu616Asp	missense_variant	11/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.0047
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;D;.;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.1	.;.;.;M;M;.;M;M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.087	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.43	.;.;.;T;.;.;T;.;T;T
Polyphen		0.0070, 0.0060	.;.;.;B;B;.;B;B;B;.
Vest4		0.49, 0.75, 0.49, 0.43
MutPred		0.20		.;Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);
MVP		0.90
MPC		1.6
ClinPred		0.82	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.65

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: rs1057519529; hg19: chr2-166900374;