chrX-41542805-G-A

Variant names:

• chrX-41542805-G-A
• rs587783360
• NM_001367721.1:c.2041C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_001367721.1(CASK):​c.2041C>T​(p.Arg681*) variant causes a stop gained, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R681R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CASK NM_001367721.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9743
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.55
• Publications: 4 publications found

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]

CASK Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant X-41542805-G-A is Pathogenic according to our data. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542805-G-A is described in CliVar as Pathogenic. Clinvar id is 158069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.2041C>T	p.Arg681*	stop_gained, splice_region_variant	Exon 22 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.2041C>T	p.Arg681*	stop_gained, splice_region_variant	Exon 22 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 984073 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 275955

African (AFR) AF: 0.00 AC: 0 AN: 24326

American (AMR) AF: 0.00 AC: 0 AN: 34773

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18577

East Asian (EAS) AF: 0.00 AC: 0 AN: 29738

South Asian (SAS) AF: 0.00 AC: 0 AN: 50356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3864

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 739959

Other (OTH) AF: 0.00 AC: 0 AN: 42368

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:3

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASK c.2041C>T (p.Arg681X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182747 control chromosomes (gnomAD). c.2041C>T has been reported in the literature as a de novo occurrence in an individual affected with features of Syndromic X-Linked Intellectual Disability Najm Type (Murakami_2019). The following publication has been ascertained in the context of this evaluation (PMID: 31044082). ClinVar contains an entry for this variant (Variation ID: 158069). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 28, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 03, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R681X pathogenic variant in the CASK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R681X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R681X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	44
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.6
Vest4		0.97
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587783360; hg19: chrX-41402058;