chr2-166044009-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP2PP3_ModeratePP5BS2
The NM_001165963.4(SCN1A):c.1703G>A(p.Arg568Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 4.88
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
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, 0.859
PP5
Variant 2-166044009-C-T is Pathogenic according to our data. Variant chr2-166044009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193841.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
BS2
High AC in GnomAdExome4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1703G>A | p.Arg568Gln | 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.1703G>A | p.Arg568Gln | missense_variant | 14/29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.1703G>A | p.Arg568Gln | missense_variant | 13/28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.1703G>A | p.Arg568Gln | missense_variant | 11/26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.1703G>A | p.Arg568Gln | missense_variant | 11/26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251104Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135682
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727236
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2022 | Reported in two unrelated patients with epilepsy in published literature (Arafat et al., 2017; Butler et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains.; This variant is associated with the following publications: (PMID: 25348405, 18804930, 29056246, 28387369) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 16, 2017 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 568 of the SCN1A protein (p.Arg568Gln). This variant is present in population databases (rs794727025, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of SCN1A-related conditions (PMID: 28387369, 29056246; Invitae). ClinVar contains an entry for this variant (Variation ID: 193841). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;D;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;M;M;.;M;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
.;.;.;D;.;.;D;.;D;D
Sift4G
Benign
.;.;.;T;.;.;T;.;T;T
Polyphen
1.0, 1.0
.;.;.;D;D;.;D;D;D;.
Vest4
0.72, 0.66, 0.69, 0.62
MutPred
0.38
.;Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);
MVP
0.97
MPC
1.8
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at