rs751979396
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1
This summary comes from the ClinGen Evidence Repository: The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6571849/MONDO:0100038/070
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.4687A>G | p.Ile1563Val | missense_variant | 26/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.4687A>G | p.Ile1563Val | missense_variant | 26/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.4564A>G | p.Ile1522Val | missense_variant | 25/26 | ||
SCN8A | NM_001369788.1 | c.4564A>G | p.Ile1522Val | missense_variant | 25/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4687A>G | p.Ile1563Val | missense_variant | 26/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.4687A>G | p.Ile1563Val | missense_variant | 26/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152224Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249196Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135198
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461710Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727138
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152224Hom.: 1 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2020 | - - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1563 of the SCN8A protein (p.Ile1563Val). This variant is present in population databases (rs751979396, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 568706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN8A protein function with a negative predictive value of 95%. 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. - |
Complex neurodevelopmental disorder Benign:1
Benign, reviewed by expert panel | curation | ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen | May 09, 2024 | The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at