X-41520515-T-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001367721.1(CASK):c.2686A>G(p.Asn896Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 23)
Consequence
CASK
NM_001367721.1 missense
NM_001367721.1 missense
Scores
7
6
4
Clinical Significance
Conservation
PhyloP100: 7.67
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASK. . Gene score misZ: 4.2502 (greater than the threshold 3.09). The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. GenCC has associacion of the gene with syndromic X-linked intellectual disability Najm type, X-linked syndromic intellectual disability, developmental and epileptic encephalopathy, FG syndrome 4.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CASK | NM_001367721.1 | c.2686A>G | p.Asn896Asp | missense_variant | 27/27 | ENST00000378163.7 | NP_001354650.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2022 | 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; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;.;.;T;.;.;.;.;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
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
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;.;.;.;D;.;D;.;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
.;T;.;.;.;D;.;D;.;.;.;.;.;T
Sift4G
Uncertain
.;.;.;.;.;D;.;D;.;.;.;.;.;.
Polyphen
D;P;.;D;.;D;.;D;.;.;.;.;.;.
Vest4
0.85
MutPred
0.73
.;.;.;.;.;.;.;Gain of disorder (P = 0.1988);.;.;.;.;.;.;
MVP
0.91
MPC
2.4
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
Publications
No publications associated with this variant yet.