rs1555226280
Variant summary
Our verdict is Pathogenic. The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate
The NM_001330260.2(SCN8A):c.3448C>T (p.Gln1150*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SCN8A
NM_001330260.2 stop_gained
NM_001330260.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.89
Publications
0 publications found
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]
SCN8A Gene-Disease associations (from GenCC):
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
- developmental and epileptic encephalopathy, 13Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
- cognitive impairment with or without cerebellar ataxiaInheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- seizures, benign familial infantile, 5Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- benign familial infantile epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- undetermined early-onset epileptic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- myoclonus, familial, 2Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_001330260.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Specifications for SCN8A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 points.
PVS1
Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 18 of 27) at amino acid 1150 of 1980, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
PM2
Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
PP5
ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN8A | MANE Select | c.3448C>T | p.Gln1150* | stop_gained | Exon 18 of 27 | NP_001317189.1 | Q9UQD0-2 | ||
| SCN8A | MANE Plus Clinical | c.3448C>T | p.Gln1150* | stop_gained | Exon 18 of 27 | NP_055006.1 | Q9UQD0-1 | ||
| SCN8A | c.3448C>T | p.Gln1150* | stop_gained | Exon 18 of 26 | NP_001171455.1 | Q9UQD0-5 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN8A | TSL:1 MANE Plus Clinical | c.3448C>T | p.Gln1150* | stop_gained | Exon 18 of 27 | ENSP00000346534.4 | Q9UQD0-1 | ||
| SCN8A | TSL:5 MANE Select | c.3448C>T | p.Gln1150* | stop_gained | Exon 18 of 27 | ENSP00000487583.2 | Q9UQD0-2 | ||
| SCN8A | TSL:5 | c.3481C>T | p.Gln1161* | stop_gained | Exon 17 of 26 | ENSP00000476447.3 | Q9UQD0-3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1454790Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 722648
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1454790
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
722648
African (AFR)
AF:
AC:
0
AN:
33378
American (AMR)
AF:
AC:
0
AN:
43870
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25994
East Asian (EAS)
AF:
AC:
0
AN:
39560
South Asian (SAS)
AF:
AC:
0
AN:
84174
European-Finnish (FIN)
AF:
AC:
0
AN:
53070
Middle Eastern (MID)
AF:
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1108830
Other (OTH)
AF:
AC:
0
AN:
60174
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)
AF:
AC:
6
AN:
25252
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Inborn genetic diseases (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs1555226280 ;
hg19: chr12-52163727;