rs781515976
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BS1_Supporting
The NM_000334.4(SCN4A):βc.5420_5425delβ(p.Leu1807_Met1808del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,612,282 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.00030 ( 0 hom., cov: 32)
Exomes π: 0.000038 ( 0 hom. )
Consequence
SCN4A
NM_000334.4 inframe_deletion
NM_000334.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.652
Genes affected
SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_000334.4.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000377 (55/1460086) while in subpopulation AFR AF= 0.00141 (47/33372). AF 95% confidence interval is 0.00109. There are 0 homozygotes in gnomad4_exome. There are 21 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.5420_5425del | p.Leu1807_Met1808del | inframe_deletion | 24/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.5420_5425del | p.Leu1807_Met1808del | inframe_deletion | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000302 AC: 46AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000765 AC: 19AN: 248366Hom.: 0 AF XY: 0.0000742 AC XY: 10AN XY: 134850
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GnomAD4 exome AF: 0.0000377 AC: 55AN: 1460086Hom.: 0 AF XY: 0.0000289 AC XY: 21AN XY: 726244
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GnomAD4 genome ? AF: 0.000302 AC: 46AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 08, 2015 | - - |
Hyperkalemic periodic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This variant, c.5420_5425del, results in the deletion of 2 amino acid(s) of the SCN4A protein (p.Leu1807_Met1808del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs781515976, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 212133). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 01, 2022 | - - |
SCN4A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 25, 2023 | The SCN4A c.5420_5425del6 variant is predicted to result in an in-frame deletion (p.Leu1807_Met1808del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-62018216-GGCATCA-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at