rs1556014749

Variant names:

• chrX-41665359-A-G
• rs1556014749
• NM_001367721.1:c.626T>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001367721.1(CASK):​c.626T>C​(p.Leu209Pro) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.2502 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Najm type, X-linked syndromic intellectual disability, developmental and epileptic encephalopathy, FG syndrome 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant X-41665359-A-G is Pathogenic according to our data. Variant chrX-41665359-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41665359-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.626T>C	p.Leu209Pro	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.626T>C	p.Leu209Pro	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Pathogenic:2

Nov 11, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2017

Laboratory for Cytogenetics and Genome Research, KU Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

de novo variant in individual with severe postnatal microcephaly, delayed psychomotor development, nystagmus, etc -

not provided Pathogenic:1

Jun 20, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L209P variant in the CASK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L209P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L209P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L209P as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.8	H;H;.;H;.;.;H;.;.;.;H;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.5	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0010	.;D;.;.;.;.;D;.;D;D;D;D;.;.;.
Polyphen		1.0	D;D;.;D;.;.;D;.;.;.;.;.;.;.;.
Vest4		0.96, 0.96, 0.96, 0.98, 0.96, 0.97
MutPred		0.69		Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);.;.;Loss of catalytic residue at L209 (P = 0.0535);.;Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);Loss of catalytic residue at L209 (P = 0.0535);.;.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs1556014749; hg19: chrX-41524612;