rs1556121425

Variant names:

• chrX-41787265-C-T
• rs1556121425
• NM_001367721.1:c.191G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367721.1(CASK):​c.191G>A​(p.Ser64Asn) 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• 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), 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.191G>A	p.Ser64Asn	missense_variant	Exon 3 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.191G>A	p.Ser64Asn	missense_variant	Exon 3 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1059879 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 330323

African (AFR) AF: 0.00 AC: 0 AN: 25727

American (AMR) AF: 0.00 AC: 0 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19153

East Asian (EAS) AF: 0.00 AC: 0 AN: 30015

South Asian (SAS) AF: 0.00 AC: 0 AN: 53284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40371

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 807297

Other (OTH) AF: 0.00 AC: 0 AN: 44837

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 27, 2017

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. This sequence change replaces serine with asparagine at codon 64 of the CASK protein (p.Ser64Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CASK-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;.;.;.;.;.;T;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N;N;.;N;.;.;N;.;.;.;N;.;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.60	.;N;.;.;.;.;N;.;N;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.11	.;T;.;.;.;.;T;.;T;T;T;T;.;.
Sift4G	Benign	0.21	.;T;.;.;.;.;T;.;T;T;T;T;.;.
Polyphen		0.016	B;B;.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.60, 0.58, 0.59, 0.59, 0.57
MutPred		0.54		Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);.;.;Loss of phosphorylation at S64 (P = 0.0333);.;Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);Loss of phosphorylation at S64 (P = 0.0333);.;Loss of phosphorylation at S64 (P = 0.0333);
MVP		0.70
MPC		1.0
ClinPred		0.64	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.91
Mutation Taster		=51/49	polymorphism

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: rs1556121425; hg19: chrX-41646518;