chrX-41853205-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001367721.1(CASK):c.82C>T(p.Arg28*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CASK
NM_001367721.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.52

Publications

5 publications found

Variant links:

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

CASK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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. There are 128 pathogenic variants in the truncated region.

PP5

Variant X-41853205-G-A is Pathogenic according to our data. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41853205-G-A is described in CliVar as Pathogenic. Clinvar id is 158086.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 link	c.82C>T	p.Arg28*	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 link	c.82C>T	p.Arg28*	stop_gained	Exon 2 of 27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1083325

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349865

African (AFR)

AF:

0.00

AC:

AN:

26177

American (AMR)

AF:

0.00

AC:

AN:

35189

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19298

East Asian (EAS)

AF:

0.00

AC:

AN:

30120

South Asian (SAS)

AF:

0.00

AC:

AN:

53781

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39823

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829193

Other (OTH)

AF:

0.00

AC:

AN:

45650

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000902

AC:

AN:

110890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33148

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30470

American (AMR)

AF:

0.00

AC:

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2615

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52925

Other (OTH)

AF:

0.00

AC:

AN:

1499

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type

Pathogenic:3

Mar 24, 2023

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as de novo. Criteria applied: PVS1, PS2_MOD, PS4_MOD, PM2_SUP. -

not provided

Pathogenic:2

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2020

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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32696595, 24781210, 28944139) -

Inborn genetic diseases

Pathogenic:1

Nov 21, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R28* pathogenic mutation (also known as c.82C>T), located in coding exon 2 of the CASK gene, results from a C to T substitution at nucleotide position 82. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation was reported as de novo in a female with intellectual disability, neurosensory deafness, microcephaly, and later onset infantile spasms (Michaud JL et al. Hum. Mol. Genet., 2014 Sep;23:4846-58). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

FG syndrome 4

Pathogenic:1

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with CASK related disorder (ClinVar ID: VCV000158086).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Intellectual disability, CASK-related, X-linked

Pathogenic:1

Sep 27, 2022

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.Arg28*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158086). This premature translational stop signal has been observed in individual(s) with clinical features of CASK-related conditions (PMID: 24781210). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.91

PhyloP100

2.5

Vest4

0.87, 0.95, 0.87, 0.95, 0.95

GERP RS

5.4

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over