chr12-51721864-A-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001330260.2(SCN8A):c.1954A>T(p.Ile652Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,574 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SCN8A
NM_001330260.2 missense
NM_001330260.2 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 1.98
Genes affected
SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.436 (greater than threshold 3.09). GenCC has associacion of gene with myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.
BP4
Computational evidence support a benign effect (MetaRNN=0.41694623).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.1954A>T | p.Ile652Phe | missense_variant | 12/27 | ENST00000627620.5 | NP_001317189.1 | |
SCN8A | NM_014191.4 | c.1954A>T | p.Ile652Phe | missense_variant | 12/27 | ENST00000354534.11 | NP_055006.1 | |
SCN8A | NM_001177984.3 | c.1954A>T | p.Ile652Phe | missense_variant | 12/26 | NP_001171455.1 | ||
SCN8A | NM_001369788.1 | c.1954A>T | p.Ile652Phe | missense_variant | 12/26 | NP_001356717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.1954A>T | p.Ile652Phe | missense_variant | 12/27 | 1 | NM_014191.4 | ENSP00000346534.4 | ||
SCN8A | ENST00000627620.5 | c.1954A>T | p.Ile652Phe | missense_variant | 12/27 | 5 | NM_001330260.2 | ENSP00000487583.2 | ||
SCN8A | ENST00000599343.5 | c.1954A>T | p.Ile652Phe | missense_variant | 11/26 | 5 | ENSP00000476447.3 | |||
SCN8A | ENST00000355133.7 | c.1954A>T | p.Ile652Phe | missense_variant | 11/25 | 1 | ENSP00000347255.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450348Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 721954
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 26, 2024 | The c.1954A>T (p.I652F) alteration is located in exon 12 (coding exon 11) of the SCN8A gene. This alteration results from a A to T substitution at nucleotide position 1954, causing the isoleucine (I) at amino acid position 652 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 30, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 652 of the SCN8A protein (p.Ile652Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;L;L;L;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;D;.;.;.
REVEL
Uncertain
Sift
Uncertain
.;D;D;D;.;.;.
Sift4G
Benign
.;T;T;T;T;T;T
Polyphen
0.89, 0.89
.;P;.;.;P;.;.
Vest4
0.52, 0.49, 0.47, 0.61, 0.50
MVP
0.83
MPC
2.0
ClinPred
D
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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