rs1057520169
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000334.4(SCN4A):āc.4415T>Cā(p.Leu1472Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L1472L) has been classified as Likely benign.
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.4415T>C | p.Leu1472Pro | missense_variant | 24/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.4415T>C | p.Leu1472Pro | missense_variant | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461644Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727076
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 08, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 25, 2020 | - - |
Hyperkalemic periodic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2020 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1472 of the SCN4A protein (p.Leu1472Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has not been reported in the literature in individuals with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 377232). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at