rs121918744

Variant names:

• chr2-165992221-G-A
• rs121918744
• NM_001165963.4:c.5054C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-165992221-G-A
• chr2-165992221-G-T

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.5054C>T​(p.Ala1685Val) 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: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 9.81

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 repeat IV (size 298) in uniprot entity SCN1A_HUMAN there are 62 pathogenic changes around while only 3 benign (95%) 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, 0.961
• PP5: Variant 2-165992221-G-A is Pathogenic according to our data. Variant chr2-165992221-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68648.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.5054C>T	p.Ala1685Val	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5054C>T	p.Ala1685Val	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5054C>T	p.Ala1685Val	missense_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5021C>T	p.Ala1674Val	missense_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4970C>T	p.Ala1657Val	missense_variant	Exon 26 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Mar 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces alanine with valine at codon 1685 of the SCN1A protein (p.Ala1685Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with SCN1A-related conditions (PMID: 11823106). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68648). This variant is also known as c.5021C>T (Ala1674Val). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. Experimental studies have shown that this variant affects SCN1A protein function (PMID: 14672992, 22525008). This variant disrupts the p.Ala1685 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22525008, 12566275). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Generalized epilepsy with febrile seizures plus, type 1 Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Severe myoclonic epilepsy in infancy Other:1

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Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;.;.;H;.;H;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;.;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.77, 0.77, 0.75, 0.85
MutPred		0.81		.;.;.;Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);.;.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.69
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: rs121918744; hg19: chr2-166848731;