NM_001367721.1:c.2470C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_001367721.1(CASK):c.2470C>T(p.Arg824Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000479 in 1,209,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. R824Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000049 ( 0 hom. 18 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.36

Publications

3 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), 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

CASK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

BP6

Variant X-41531057-G-A is Benign according to our data. Variant chrX-41531057-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 590126.

BS2

High AC in GnomAdExome4 at 54 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.2470C>T	p.Arg824Trp	missense_variant	Exon 25 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7 link	c.2470C>T	p.Arg824Trp	missense_variant	Exon 25 of 27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000650

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000382

AC:

AN:

183463

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000721

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1097952

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363308

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26397

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000487

AC:

AN:

841868

Other (OTH)

AF:

0.000152

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000357

AC:

AN:

111960

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34130

show subpopulations

African (AFR)

AF:

0.0000650

AC:

AN:

30789

American (AMR)

AF:

0.00

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6035

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53208

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Observed in 0.004% (8/200477 alleles) in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24893065) -

Oct 10, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 29, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, CASK-related, X-linked

Benign:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;.;.;.;.;.;.;T;.;.;.;.;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.070

MutationAssessor

Pathogenic

3.6

.;.;.;.;.;.;.;H;.;.;.;.;.;.

PhyloP100

6.4

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.4

.;.;.;.;.;D;.;D;.;.;.;.;.;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

.;.;.;.;.;D;.;D;.;.;.;.;.;.

Sift4G

Uncertain

0.0020

.;.;.;.;.;D;.;D;.;.;.;.;.;.

Polyphen

1.0

D;D;.;D;.;D;.;D;.;.;.;.;.;.

Vest4

0.92

MVP

0.91

MPC

2.3

ClinPred

0.98

GERP RS

4.7

Varity_R

0.98

gMVP

0.86

Mutation Taster

=5/95

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over