chrX-41665368-C-T

Variant names:

• chrX-41665368-C-T
• rs587783367
• NM_001367721.1:c.617G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001367721.1(CASK):​c.617G>A​(p.Gly206Asp) 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. 12/21 in silico tools predict a damaging 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. G206S) has been classified as Likely pathogenic.

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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-41665369-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 976147.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant X-41665368-C-T is Pathogenic according to our data. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080. Variant chrX-41665368-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158080.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.617G>A	p.Gly206Asp	missense_variant	Exon 7 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.617G>A	p.Gly206Asp	missense_variant	Exon 7 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:1 Uncertain:1

-

Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;H;.;.;H;.;.;.;H;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Polyphen		1.0	D;D;.;D;.;.;D;.;.;.;.;.;.;.;.
Vest4		0.96, 0.98, 0.98, 0.98
MutPred		0.85		Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);.;.;Loss of catalytic residue at I208 (P = 0.1156);.;Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);Loss of catalytic residue at I208 (P = 0.1156);.;.;.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.0074	Neutral
Varity_R		1.0
gMVP		1.0
Mutation Taster		=23/77	disease causing

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: rs587783367; hg19: chrX-41524621;