X-41589562-G-C

Variant names:

• chrX-41589562-G-C
• rs137852820
• NM_001367721.1:c.1186C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367721.1(CASK):​c.1186C>G​(p.Pro396Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,202,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P396S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 11 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3483488).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.1186C>G	p.Pro396Ala	missense	Exon 13 of 27	NP_001354650.1
	CASK	NM_003688.4		c.1186C>G	p.Pro396Ala	missense	Exon 13 of 27	NP_003679.2
	CASK	NM_001410745.1		c.1168C>G	p.Pro390Ala	missense	Exon 12 of 26	NP_001397674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.1186C>G	p.Pro396Ala	missense	Exon 13 of 27	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.1186C>G	p.Pro396Ala	missense	Exon 12 of 25	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.1168C>G	p.Pro390Ala	missense	Exon 12 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112279 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090388 Hom.: 0 Cov.: 26 AF XY: 0.00000281 AC XY: 1 AN XY: 356232

African (AFR) AF: 0.00 AC: 0 AN: 26262

American (AMR) AF: 0.00 AC: 0 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 30125

South Asian (SAS) AF: 0.00 AC: 0 AN: 53890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835292

Other (OTH) AF: 0.0000218 AC: 1 AN: 45839

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112334 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34520

African (AFR) AF: 0.00 AC: 0 AN: 30969

American (AMR) AF: 0.00 AC: 0 AN: 10576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000277 AC: 1 AN: 3610

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53285

Other (OTH) AF: 0.00 AC: 0 AN: 1530

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 26, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CASK protein function. This variant has not been reported in the literature in individuals affected with CASK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 396 of the CASK protein (p.Pro396Ala).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PhyloP100		9.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.38	T
Sift4G	Benign	0.47	T
Polyphen		0.013	B
Vest4		0.46
MutPred		0.41		Loss of methylation at K393 (P = 0.0592)
MVP		0.82
MPC		1.0
ClinPred		0.59	D
GERP RS		5.8
Varity_R		0.14
gMVP		0.59
Mutation Taster		=72/28	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: rs137852820; hg19: chrX-41448815;