rs1114167352
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP2PP5_Very_Strong
The NM_001367721.1(CASK):c.1465C>T(p.Arg489Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R489Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 22)
Consequence
CASK
NM_001367721.1 missense
NM_001367721.1 missense
Scores
8
2
1
Clinical Significance
Conservation
PhyloP100: 6.38
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;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-41578377-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, CASK
PP5
?
Variant X-41578378-G-A is Pathogenic according to our data. Variant chrX-41578378-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASK | NM_001367721.1 | c.1465C>T | p.Arg489Trp | missense_variant | 15/27 | ENST00000378163.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASK | ENST00000378163.7 | c.1465C>T | p.Arg489Trp | missense_variant | 15/27 | 5 | NM_001367721.1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability Najm type Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | May 28, 2018 | - - |
Smith-Magenis Syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 15, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27799067, 33090494, 32313833) - |
CASK-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as pathogenic and reported on 12/21/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the 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
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4
0.85, 0.78
MutPred
0.50
.;Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;.;Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;.;.;Loss of disorder (P = 0.0062);.;.;.;
MVP
0.93
MPC
2.3
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