rs1556121425
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001367721.1(CASK):c.191G>A(p.Ser64Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
CASK
NM_001367721.1 missense
NM_001367721.1 missense
Scores
3
3
6
Clinical Significance
Conservation
PhyloP100: 7.48
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CASK
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASK | NM_001367721.1 | c.191G>A | p.Ser64Asn | missense_variant | 3/27 | ENST00000378163.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASK | ENST00000378163.7 | c.191G>A | p.Ser64Asn | missense_variant | 3/27 | 5 | NM_001367721.1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1059879Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 330323
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1059879
Hom.:
Cov.:
25
AF XY:
AC XY:
0
AN XY:
330323
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, CASK-related, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2017 | 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CASK-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 64 of the CASK protein (p.Ser64Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;N;.;.;N;.;.;.;N;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
B;B;.;B;.;.;.;.;.;.;.;.;.;.
Vest4
0.60, 0.58, 0.59, 0.59, 0.57
MutPred
Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);.;.;Loss of phosphorylation at S64 (P = 0.0333);.;Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);.;Loss of phosphorylation at S64 (P = 0.0333);
MVP
0.70
MPC
1.0
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