2-165994164-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PP2PP3BP4_ModerateBP6BS2
The NM_001165963.4(SCN1A):c.4834G>A(p.Val1612Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,610,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 7.82
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)
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 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
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
Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.25920174).
BP6
Variant 2-165994164-C-T is Benign according to our data. Variant chr2-165994164-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68638.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, not_provided=1}.
BS2
High AC in GnomAdExome4 at 39 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4834G>A | p.Val1612Ile | missense_variant | 28/29 | ENST00000674923.1 | NP_001159435.1 | |
LOC102724058 | NR_110598.1 | n.176-21449C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4834G>A | p.Val1612Ile | missense_variant | 28/29 | NM_001165963.4 | ENSP00000501589 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-21449C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151920Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000174 AC: 43AN: 247462Hom.: 0 AF XY: 0.000157 AC XY: 21AN XY: 133784
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1458406Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 725438
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 151920Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74202
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Severe myoclonic epilepsy in infancy Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2018 | The p.V1612I variant (also known as c.4834G>A), located in coding exon 25 of the SCN1A gene, results from a G to A substitution at nucleotide position 4834. The valine at codon 1612 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in three individuals with Dravet syndrome; in two of the individuals, it was inherited from parents (Depienne C et al. J. Med. Genet., 2009 Mar;46:183-91; Herini ES et al. Pediatr Int, 2010 Apr;52:234-9; Kwong AK et al. PLoS ONE, 2012 Jul;7:e41802). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.02% (46/273258) total alleles studied. The highest observed frequency was 0.24% (44/18572) of East Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
Plagiocephaly;C0431352:Secondary microcephaly;C0543888:Epileptic encephalopathy;C0557874:Global developmental delay;C0684276:Hypsarrhythmia;C1836806:Mild microcephaly;C1858120:Generalized hypotonia;C3665347:Visual impairment;C3887898:Infantile spasms;C4021160:Posterior plagiocephaly;C4048268:Cerebral visual impairment Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;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
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;M;.;.;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;.;.;N;.;.;N;.;N;N
REVEL
Pathogenic
Sift
Uncertain
.;.;.;D;.;.;D;.;D;D
Sift4G
Uncertain
.;.;.;D;.;.;D;.;D;D
Polyphen
1.0
.;.;.;.;D;.;.;D;D;.
Vest4
0.93, 0.93, 0.93
MutPred
0.70
.;.;.;Gain of catalytic residue at L1614 (P = 0.363);.;.;Gain of catalytic residue at L1614 (P = 0.363);.;.;.;
MVP
1.0
MPC
1.3
ClinPred
T
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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