rs137852815

chrX-41553843-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001367721.1(CASK):c.1915C>T(p.Arg639Ter) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CASK NM_001367721.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant X-41553843-G-A is Pathogenic according to our data. Variant chrX-41553843-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11530.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.1915C>T	p.Arg639Ter	stop_gained	21/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.1915C>T	p.Arg639Ter	stop_gained	21/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

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:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The hemizygous p.Arg639Ter variant in CASK was identified by our study in 1 individual with mental retardation and microcephaly with pontine and cerebellar hypoplasia. Trio exome analysis showed this variant to be de novo. The variant has been reported in 1 Turkish individual with mental retardation and microcephaly with pontine and cerebellar hypoplasia (PMID: 19165920), but was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 11530) as pathogenic by OMIM and GeneDx. This nonsense variant leads to a premature termination codon at position 639, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CASK gene is an established disease mechanism in mental retardation and microcephaly with pontine and cerebellar hypoplasia. In summary, this variant meets criteria to be classified as pathogenic for mental retardation and microcephaly with pontine and cerebellar hypoplasia in an X-linked dominant manner based on the predicted impact of the variant, and occurrences in affected individuals while absent from control populations. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting, PS2 (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2016	The R639X pathogenic variant in the CASK gene has been reported previously as a de novo pathogenic variant in association with intellectual disability, microcephaly, and pontine and cerebellar hypoplasia in a female (Najm et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R639X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret R639X as a pathogenic variant consistent. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	39
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.74	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.96
GERP RS		5.2

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

Other links and lift over

dbSNP: rs137852815; hg19: chrX-41413096;