rs141840001

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001367721.1(CASK):c.1718C>T(p.Thr573Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,209,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 hemizygotes in GnomAD. In-silico tool predicts a benign 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. T573S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 0 hom. 51 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.55

Publications

2 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35213417).

BP6

Variant X-41559798-G-A is Benign according to our data. Variant chrX-41559798-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194841.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000711 (8/112534) while in subpopulation NFE AF = 0.000112 (6/53359). AF 95% confidence interval is 0.0000483. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.1718C>T	p.Thr573Ile	missense_variant	Exon 18 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.1718C>T	p.Thr573Ile	missense_variant	Exon 18 of 27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.0000711

AC:

AN:

112534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

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:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000112

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000660

AC:

AN:

181937

AF XY:

0.000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

167

AN:

1096581

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

361987

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26376

American (AMR)

AF:

0.00

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53929

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.000191

AC:

161

AN:

840822

Other (OTH)

AF:

0.0000869

AC:

AN:

46035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000711

AC:

AN:

112534

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

34678

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30943

American (AMR)

AF:

0.00

AC:

AN:

10652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3604

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.000163

AC:

AN:

6150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000112

AC:

AN:

53359

Other (OTH)

AF:

0.00

AC:

AN:

1514

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 Het

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:

0.000212

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 24, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, CASK-related, X-linked

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

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

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.0

.;N;.;N;.;.;.;N;.;.;.;N;.;.;.

PhyloP100

6.5

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.6

.;.;.;.;.;D;.;N;.;.;.;N;.;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.030

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

Polyphen

0.67

P;B;.;B;.;B;.;B;.;.;.;.;.;.;.

Vest4

0.33, 0.40

MVP

0.81

MPC

1.1

ClinPred

0.21

GERP RS

6.0

Varity_R

0.41

gMVP

0.65

Mutation Taster

=83/17

polymorphism

(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