rs779508996

Positions:

• chrX-41555605-G-A
• chrX-41555605-G-T

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.1837C>T​(p.Arg613Ter) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CASK NM_001367721.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.00

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-41555605-G-A is Pathogenic according to our data. Variant chrX-41555605-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41555605-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1	c.1837C>T	p.Arg613Ter	stop_gained	20/27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.1837C>T	p.Arg613Ter	stop_gained	20/27	5	NM_001367721.1	ENSP00000367405	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jun 09, 2021	PVS1, PS4_moderate, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 14, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27652284, 28944139, 29878067) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2019	- -

FG syndrome 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

- -

Intellectual disability, CASK-related, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Arg613*) in the CASK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASK are known to be pathogenic (PMID: 19165920, 20029458, 21954287, 22452838, 22709267). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of CASK-related conditions (PMID: 27652284, 29878067). In at least one individual the variant was observed to be de novo. This variant is also known as c.1768C>T (p.R584Ter). ClinVar contains an entry for this variant (Variation ID: 418109). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;D;D
Vest4		0.89
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs779508996; hg19: chrX-41414858; COSMIC: COSV59367508; COSMIC: COSV59367508;