2-166002729-C-G

Variant names:

• chr2-166002729-C-G
• rs796053006
• NM_001165963.4:c.4027G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001165963.4(SCN1A):​c.4027G>C​(p.Ala1343Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 16) in uniprot entity SCN1A_HUMAN there are 5 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 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, 0.984
• PP5: Variant 2-166002729-C-G is Pathogenic according to our data. Variant chr2-166002729-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 206819.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4027G>C	p.Ala1343Pro	missense_variant	Exon 24 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4027G>C	p.Ala1343Pro	missense_variant	Exon 24 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4027G>C	p.Ala1343Pro	missense_variant	Exon 23 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3994G>C	p.Ala1332Pro	missense_variant	Exon 21 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3943G>C	p.Ala1315Pro	missense_variant	Exon 21 of 26	5		ENSP00000386312.1

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

not provided Pathogenic:1

Jun 07, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1343Pro (GCA>CCA): c.4027 G>C in exon 21 of the SCN1A gene (NM_001165963.1) The Ala1343Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ala1343Pro in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although Alanine and Proline are both uncharged non-polar amino acids, the gain of a bulky Proline residue may alter the secondary structure of the protein. Ala1343Pro alters a highly conserved highly conserved position in the linker region between the fourth and fifth segments of the third transmembrane domain of the Nav1.1 protein, and other missense mutations in this region have been reported in association with epilepsy in an external mutation database. Multiple in silico models predict that Ala1343Pro is damaging to protein structure/function. This variant has been observed de novo with confirmed parentage. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	5.1	.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;D;D;.;D;D;D;.
Vest4		0.97, 0.98, 0.98, 0.98
MutPred		0.89		.;.;Loss of catalytic residue at A1343 (P = 0.0755);.;.;Loss of catalytic residue at A1343 (P = 0.0755);.;.;.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		1.0

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: rs796053006; hg19: chr2-166859239;