rs587783367

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001367721.1(CASK):​c.617G>A​(p.Gly206Asp) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

CASK
NM_001367721.1 missense

Scores

14
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.57
Variant links:
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 Likely_pathogenic. Variant got 8 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). GenCC has associacion of 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, 0.972
PP5
Variant X-41665368-C-T is Pathogenic according to our data. Variant chrX-41665368-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158080.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASKNM_001367721.1 linkuse as main transcriptc.617G>A p.Gly206Asp missense_variant 7/27 ENST00000378163.7 NP_001354650.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASKENST00000378163.7 linkuse as main transcriptc.617G>A p.Gly206Asp missense_variant 7/275 NM_001367721.1 ENSP00000367405 A1O14936-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H;H;.;H;.;.;H;.;.;.;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-4.8
.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Sift4G
Pathogenic
0.0
.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Polyphen
1.0
D;D;.;D;.;.;D;.;.;.;.;.;.;.;.
Vest4
0.96, 0.98, 0.98, 0.98
MutPred
0.85
Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);.;.;Loss of catalytic residue at I208 (P = 0.1156);.;Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);.;.;.;
MVP
1.0
MPC
2.5
ClinPred
1.0
D
GERP RS
5.7
Varity_R
1.0
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587783367; hg19: chrX-41524621; API