Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001367721.1(CASK):c.2317+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,169,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 55 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).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., 27 hem., cov: 23)

Exomes 𝑓: 0.000093 ( 0 hom. 28 hem. )

Consequence

CASK
NM_001367721.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.37

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), 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-41534697-A-G is Benign according to our data. Variant chrX-41534697-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287834.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000788 (88/111731) while in subpopulation AFR AF = 0.0027 (83/30781). AF 95% confidence interval is 0.00223. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 88 XL,AD gene.

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	Effect	Exon Rank	Protein
CASK	NM_001367721.1	MANE Select	c.2317+9T>C	intron	N/A	NP_001354650.1
CASK	NM_003688.4		c.2302+9T>C	intron	N/A	NP_003679.2
CASK	NM_001410745.1		c.2299+9T>C	intron	N/A	NP_001397674.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CASK	ENST00000378163.7	TSL:5 MANE Select	c.2317+9T>C	intron	N/A	ENSP00000367405.1
CASK	ENST00000421587.8	TSL:1	c.2248+9T>C	intron	N/A	ENSP00000400526.4
CASK	ENST00000378166.9	TSL:1	c.2215+9T>C	intron	N/A	ENSP00000367408.5

Frequencies

GnomAD3 genomes

AF:

0.000788

AC:

AN:

111678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.00

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.000229

AC:

AN:

183216

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000926

AC:

AN:

1057868

Hom.:

Cov.:

AF XY:

0.0000848

AC XY:

AN XY:

330308

show subpopulations

African (AFR)

AF:

0.00250

AC:

AN:

25639

American (AMR)

AF:

0.000313

AC:

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19127

East Asian (EAS)

AF:

0.00

AC:

AN:

30050

South Asian (SAS)

AF:

0.0000376

AC:

AN:

53182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

805451

Other (OTH)

AF:

0.000469

AC:

AN:

44744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000788

AC:

AN:

111731

Hom.:

Cov.:

AF XY:

0.000796

AC XY:

AN XY:

33899

show subpopulations

African (AFR)

AF:

0.00270

AC:

AN:

30781

American (AMR)

AF:

0.000286

AC:

AN:

10492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3590

South Asian (SAS)

AF:

0.00

AC:

AN:

2706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53146

Other (OTH)

AF:

0.00130

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000491

Hom.:

Bravo

AF:

0.000850

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CASK-related disorder (1)

Intellectual disability, CASK-related, X-linked (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.4

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over