Genetic Variant CASK:p.Met519Thr (chrX-41569694-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001367721.1(CASK):c.1556T>C(p.Met519Thr) 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 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.49

Publications

0 publications found

Variant links:

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), G2P, Ambry Genetics
syndromic X-linked intellectual disability Najm type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CASK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	NM_001367721.1	MANE Select	c.1556T>C	p.Met519Thr	missense	Exon 16 of 27	NP_001354650.1	O14936-1
CASK	NM_003688.4		c.1556T>C	p.Met519Thr	missense	Exon 16 of 27	NP_003679.2	O14936-2
CASK	NM_001410745.1		c.1538T>C	p.Met513Thr	missense	Exon 15 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	ENST00000378163.7	TSL:5 MANE Select	c.1556T>C	p.Met519Thr	missense	Exon 16 of 27	ENSP00000367405.1	O14936-1
CASK	ENST00000421587.8	TSL:1	c.1556T>C	p.Met519Thr	missense	Exon 15 of 25	ENSP00000400526.4	A0A7I2RJN6
CASK	ENST00000378166.9	TSL:1	c.1538T>C	p.Met513Thr	missense	Exon 15 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1062423

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

333145

African (AFR)

AF:

0.00

AC:

AN:

25792

American (AMR)

AF:

0.00

AC:

AN:

34885

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19068

East Asian (EAS)

AF:

0.00

AC:

AN:

30025

South Asian (SAS)

AF:

0.00

AC:

AN:

52325

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40395

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4049

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

811015

Other (OTH)

AF:

0.00

AC:

AN:

44869

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.3

PhyloP100

8.5

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.69

Vest4

0.81

MutPred

0.66

Gain of catalytic residue at M519 (P = 0.0028)

MVP

0.97

MPC

2.2

ClinPred

1.0

GERP RS

5.1

Varity_R

0.94

gMVP

0.82

Mutation Taster

=0/100

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over