chrX-41660468-A-G

Variant names:

• chrX-41660468-A-G
• rs137852817
• NM_001367721.1:c.802T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001367721.1(CASK):​c.802T>C​(p.Tyr268His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.95
• Publications: 15 publications found

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

LOC124905180 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001367721.1
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41660468-A-G is Pathogenic according to our data. Variant chrX-41660468-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11533.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.802T>C	p.Tyr268His	missense_variant	Exon 8 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.802T>C	p.Tyr268His	missense_variant	Exon 8 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

FG syndrome 4 Pathogenic:1

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 15, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate an adverse effect on hydrogen bonds and Liprin-alpha2 binding thus affecting cell survival (Guo et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33090494, 19377476, 23406872, 24505460, 37190086) -

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

Apr 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect CASK function (PMID: 23406872, 24505460, 33090494). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 11533). This missense change has been observed in individual(s) with CASK-related conditions (PMID: 20029458). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 268 of the CASK protein (p.Tyr268His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.14	.;.;.;.;.;.;T;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.71	N;N;.;N;.;.;N;.;.;.;N;.;.;.;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.44	.;N;.;.;.;.;N;.;N;N;N;N;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.23	.;T;.;.;.;.;T;.;T;T;T;T;.;.;.
Sift4G	Benign	0.31	.;T;.;.;.;.;T;.;T;T;T;T;.;.;.
Polyphen		0.0	B;P;.;B;.;.;B;.;.;.;.;.;.;.;.
Vest4		0.67, 0.67, 0.68, 0.66, 0.67, 0.68
MutPred		0.31		Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);.;.;Loss of phosphorylation at Y268 (P = 0.0373);.;Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);Loss of phosphorylation at Y268 (P = 0.0373);.;.;.;
MVP		0.97
MPC		1.3
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.50
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852817; hg19: chrX-41519721;