rs794727270

Variant names:

• chrX-41853208-G-A
• rs794727270
• NM_001367721.1:c.79C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001367721.1(CASK):​c.79C>T​(p.Arg27*) 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CASK NM_001367721.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.96

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.972 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41853208-G-A is Pathogenic according to our data. Variant chrX-41853208-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 195200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853208-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:3

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 12, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-month-old male with hypotonia, myoclonic seizures, dysmorphic features, failure to thrive, microcephaly, brain anomalies (simplified sulcation, delayed myelination, diminutive brainstem & cerebellum), concealed penis. -

not provided Pathogenic:3

Jun 12, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 28944139, 25326635, 25886057, 22452838, 28783747, 31474318, 31069529, 32696595, 21735175, 35670295) -

Congenital cerebellar hypoplasia Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg27*) 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 CASK-related conditions (PMID: 21735175, 35670295). ClinVar contains an entry for this variant (Variation ID: 195200). 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	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.85, 0.93, 0.85, 0.94, 0.94, 0.93
GERP RS		5.4

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: rs794727270; hg19: chrX-41712461;