rs869312966
Variant summary
The NM_001330260.2(SCN8A):c.4859G>T (p.Arg1620Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005327903: Published functional studies demonstrate a damaging effect indicating that the R1620L variant reduces sodium current density and decreases neuronal firing (Liu et al., 2019)" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R1620P: Pathogenic (ClinVar VariationId 4812133, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1620*: Uncertain_significance (ClinVar VariationId 2784669, 1 star)
Frequency
Consequence
NM_001330260.2 missense
Scores
Clinical Significance
Conservation
Publications
- 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
Classification according to ACMG Germline Pathogenicity v2019
Our verdict: Pathogenic. The variant received 19 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS3Functional studies show damaging effect | Well-established functional study supports damaging effect (PS3); SCV005327903: Published functional studies demonstrate a damaging effect indicating that the R1620L variant reduces sodium current density and decreases neuronal firing (Liu et al., 2019); PMID: 30615093, 28330790 | ||
| PM1Mutational hot spot or critical domain | Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 18 pathogenic, 0 benign (OR vs. background: 185.0). | ||
| PM2Absent/extremely low in population databases | Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R1620P: Pathogenic (ClinVar VariationId 4812133, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R1620*: Uncertain_significance (ClinVar VariationId 2784669, 1 star) | ||
| PP2Missense in gene with low missense rate | Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 10.451). ClinVar shows strong pathogenic missense enrichment: 333 P/LP and 85 B/LB missense entries (ratio 3.9×). | ||
| PP3Computational evidence supports damaging effect | Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong). | ||
| PP5Reputable source reports pathogenic | ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 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.4859G>T p.Arg1620Leu | missense | Exon 27 of 27 | Prot: NP_001317189.1 UniProt: | |
SCN8A | MANE Plus Clinical | c.4859G>T p.Arg1620Leu | missense | Exon 27 of 27 | Prot: NP_055006.1 UniProt: | |
SCN8A | c.4736G>T p.Arg1579Leu | missense | Exon 26 of 26 | Prot: NP_001171455.1 UniProt: |
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
SCN8A | TSL:1MANE Plus Clinical | c.4859G>T p.Arg1620Leu | missense | Exon 27 of 27 | Prot: ENSP00000346534.4 UniProt: | |
SCN8A | TSL:5MANE Select | c.4859G>T p.Arg1620Leu | missense | Exon 27 of 27 | Prot: ENSP00000487583.2 UniProt: | |
SCN8A | TSL:5 | c.4892G>T p.Arg1631Leu | missense | Exon 26 of 26 | Prot: ENSP00000476447.3 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 3 sources | |||||
GnomAD3 genomes | Cov:32 | ||||
GnomAD4 exome | Cov:33 | ||||
GnomAD4 genome | Cov:32 | ||||
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 31 | |
AlphaMissense | Pathogenic | 0.99 | |
BayesDel_addAF | Pathogenic | 0.58 | D |
BayesDel_noAF | Pathogenic | 0.59 | |
CADD | Pathogenic | 29 | |
DANN | Uncertain | 1.0 | |
DEOGEN2 | Pathogenic | 0.98 | D |
Eigen | Pathogenic | 1.1 | |
Eigen_PC | Pathogenic | 1.0 | |
FATHMM_MKL | Pathogenic | 0.99 | D |
FuncVEP CTI | Pathogenic | 1.0 | |
GPN-Star LLR | N/A | -11 | |
GPN-Star score | N/A | 11 | |
LIST_S2 | Uncertain | 0.91 | D |
M_CAP | Pathogenic | 0.91 | D |
MetaRNN | Pathogenic | 0.98 | D |
MetaSVM | Pathogenic | 1.1 | D |
Mutation Taster | N/A | 1/99 | disease causing (ClinVar) |
MutationAssessor | Pathogenic | 4.1 | H |
PhyloP100 | Pathogenic | 10 | |
popEVE | Pathogenic | -5.9 | |
PrimateAI | Pathogenic | 0.91 | D |
PROVEAN | Pathogenic | -6.3 | D |
REVEL | Pathogenic | 0.96 | |
Sift | Pathogenic | 0.0 | D |
Sift4G | Benign | 0.065 | T |
Varity_R | N/A | 0.90 | |
VESM-3B | Benign | -16 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.0 | |
SpliceAI score (max) | Benign | 0.0 | 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.
MaveDB functional evidence
MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.