rs1556014749
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001367721.1(CASK):c.626T>C(p.Leu209Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
CASK
NM_001367721.1 missense
NM_001367721.1 missense
Scores
9
2
1
Clinical Significance
Conservation
PhyloP100: 8.95
Genes affected
CASK (HGNC:1497): (calcium/calmodulin dependent serine protein kinase) This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CASK
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.913
PP5
?
Variant X-41665359-A-G is Pathogenic according to our data. Variant chrX-41665359-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41665359-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASK | NM_001367721.1 | c.626T>C | p.Leu209Pro | missense_variant | 7/27 | ENST00000378163.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASK | ENST00000378163.7 | c.626T>C | p.Leu209Pro | missense_variant | 7/27 | 5 | NM_001367721.1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability Najm type Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Laboratory for Cytogenetics and Genome Research, KU Leuven | Nov 01, 2017 | de novo variant in individual with severe postnatal microcephaly, delayed psychomotor development, nystagmus, etc - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 11, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2017 | The L209P variant in the CASK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L209P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L209P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L209P as a likely pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;H;.;.;H;.;.;.;H;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;.;D;.;.;D;.;.;.;.;.;.;.;.
Vest4
0.96, 0.96, 0.96, 0.98, 0.96, 0.97
MutPred
Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);.;.;Loss of catalytic residue at L209 (P = 0.0535);.;Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);.;.;.;
MVP
0.99
MPC
2.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at