X-41534725-CC-AG

Variant names:

• chrX-41534725-CC-AG
• NM_001367721.1:c.2297_2298delGGinsCT
• CASK p.Arg766Pro

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001367721.1(CASK):​c.2297_2298delGGinsCT​(p.Arg766Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R766Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 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), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367721.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.2297_2298delGGinsCT	p.Arg766Pro	missense	N/A	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2282_2283delGGinsCT	p.Arg761Pro	missense	N/A	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2279_2280delGGinsCT	p.Arg760Pro	missense	N/A	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.2297_2298delGGinsCT	p.Arg766Pro	missense	N/A	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2228_2229delGGinsCT	p.Arg743Pro	missense	N/A	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2195_2196delGGinsCT	p.Arg732Pro	missense	N/A	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-41393978;