chrX-41520467-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001367721.1(CASK):c.2734C>T(p.Leu912Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,096,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L912L) has been classified as Benign.
Frequency
Consequence
NM_001367721.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASK | NM_001367721.1 | c.2734C>T | p.Leu912Phe | missense_variant | 27/27 | ENST00000378163.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASK | ENST00000378163.7 | c.2734C>T | p.Leu912Phe | missense_variant | 27/27 | 5 | NM_001367721.1 | A1 | |
CASK-AS1 | ENST00000451126.1 | n.331+101G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182820Hom.: 0 AF XY: 0.0000149 AC XY: 1AN XY: 67296
GnomAD4 exome AF: 0.0000219 AC: 24AN: 1096274Hom.: 0 Cov.: 29 AF XY: 0.0000249 AC XY: 9AN XY: 361712
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
FG syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed variant has been reported to the ClinVar database as Uncertain Significance (VUS) but not reported in any affected individual. The p.Leu912Phe variant is novel (not in any individuals) in 1000 Genomes. The amino acid Leu at position 912 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Leu912Phe in CASK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2022 | - - |
Intellectual disability, CASK-related, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2018 | 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASK-related disease. This variant is present in population databases (rs777220099, ExAC 0.01%). This sequence change replaces leucine with phenylalanine at codon 907 of the CASK protein (p.Leu907Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at