X-41636647-G-C

Variant names:

• chrX-41636647-G-C
• rs886128077
• NM_001367721.1:c.846C>G

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.846C>G​(p.Tyr282*) variant causes a stop gained change involving the alteration of a non-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 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:6
• Conservation: PhyloP100: 1.89

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]

LOC124905180 (HGNC:):

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-41636647-G-C is Pathogenic according to our data. Variant chrX-41636647-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 434588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41636647-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.846C>G	p.Tyr282*	stop_gained	Exon 9 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.846C>G	p.Tyr282*	stop_gained	Exon 9 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:2

Nov 15, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1, PS2, PS3, PM2, PM5, PP5; Variant was found in heterozygous state. De novo-status was confirmed via in-house segregation analysis. -

Sep 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jun 07, 2016

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 20, 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: 33640666, 36168867, 34085948) -

Inborn genetic diseases Pathogenic:1

Mar 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.846C>G (p.Y282*) alteration, located in exon 9 (coding exon 9) of the CASK gene, consists of a C to G substitution at nucleotide position 846. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 282. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. for x-linked dominant CASK-related microcephaly with pontine and cerebellar hypoplasia; however, its clinical significance for x-linked recessive CASK-related intellectual disability with or without nystagmus is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in a female with features consistent with CASK-related microcephaly with pontine and cerebellar hypoplasia, and RT-PCR analysis showed significantly lower levels of CASK expression than her parents and sex- and age-matched control groups (Yang, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

FG syndrome 4;C2677903:Syndromic X-linked intellectual disability Najm type;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.91, 0.98, 0.91, 0.98
GERP RS		3.4

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: rs886128077; hg19: chrX-41495900;