rs587783369

Variant names:

• chrX-41660506-C-T
• rs587783369
• NM_001367721.1:c.764G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_001367721.1(CASK):​c.764G>A​(p.Arg255His) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R255C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 7.57
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-41660507-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 421141.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant X-41660506-C-T is Pathogenic according to our data. Variant chrX-41660506-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158084.

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.764G>A	p.Arg255His	missense	Exon 8 of 27	NP_001354650.1
	CASK	NM_003688.4		c.764G>A	p.Arg255His	missense	Exon 8 of 27	NP_003679.2
	CASK	NM_001410745.1		c.764G>A	p.Arg255His	missense	Exon 8 of 26	NP_001397674.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.764G>A	p.Arg255His	missense	Exon 8 of 27	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.782G>A	p.Arg261His	missense	Exon 8 of 25	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.764G>A	p.Arg255His	missense	Exon 8 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Syndromic X-linked intellectual disability Najm type (4)
3	-	-	FG syndrome 4 (3)
2	-	-	not provided (2)
1	-	-	FG syndrome 4;C2677903:Syndromic X-linked intellectual disability Najm type (1)
-	1	-	Intellectual disability, CASK-related, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.048	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.51		Loss of MoRF binding (P = 0.0277)
MVP		0.96
MPC		2.3
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.77
gMVP		0.82
Mutation Taster		=74/26	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: rs587783369; hg19: chrX-41519759; COSMIC: COSV59370581;