rs117217073
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001330260.2(SCN8A):c.3076C>T(p.Arg1026Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,932 control chromosomes in the GnomAD database, including 183 homozygotes. 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 0.011 ( 16 hom., cov: 32)
Exomes 𝑓: 0.013 ( 167 hom. )
Consequence
SCN8A
NM_001330260.2 missense
NM_001330260.2 missense
Scores
3
9
6
Clinical Significance
Conservation
PhyloP100: 1.53
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 Benign. Variant got -12 ACMG points.
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=0.006647438).
BP6
Variant 12-51769039-C-T is Benign according to our data. Variant chr12-51769039-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130244.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr12-51769039-C-T is described in Lovd as [Likely_benign]. Variant chr12-51769039-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1629/152276) while in subpopulation NFE AF= 0.0146 (991/68024). AF 95% confidence interval is 0.0138. There are 16 homozygotes in gnomad4. There are 879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1629 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/27 | ENST00000627620.5 | NP_001317189.1 | |
SCN8A | NM_014191.4 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/27 | ENST00000354534.11 | NP_055006.1 | |
SCN8A | NM_001177984.3 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/26 | NP_001171455.1 | ||
SCN8A | NM_001369788.1 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/26 | NP_001356717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/27 | 1 | NM_014191.4 | ENSP00000346534.4 | ||
SCN8A | ENST00000627620.5 | c.3076C>T | p.Arg1026Cys | missense_variant | 17/27 | 5 | NM_001330260.2 | ENSP00000487583.2 | ||
SCN8A | ENST00000599343.5 | c.3109C>T | p.Arg1037Cys | missense_variant | 16/26 | 5 | ENSP00000476447.3 | |||
SCN8A | ENST00000355133.7 | c.3076C>T | p.Arg1026Cys | missense_variant | 16/25 | 1 | ENSP00000347255.4 |
Frequencies
GnomAD3 genomes AF: 0.0107 AC: 1630AN: 152158Hom.: 16 Cov.: 32
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GnomAD3 exomes AF: 0.0117 AC: 2916AN: 249052Hom.: 33 AF XY: 0.0119 AC XY: 1604AN XY: 135122
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GnomAD4 exome AF: 0.0127 AC: 18504AN: 1461656Hom.: 167 Cov.: 31 AF XY: 0.0127 AC XY: 9228AN XY: 727102
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GnomAD4 genome AF: 0.0107 AC: 1629AN: 152276Hom.: 16 Cov.: 32 AF XY: 0.0118 AC XY: 879AN XY: 74454
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | SCN8A: PP2, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 08, 2019 | - - |
Developmental and epileptic encephalopathy, 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Feb 14, 2020 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;.;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MPC
ClinPred
T
GERP RS
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