rs147738759

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001367721.1(CASK):c.600A>G(p.Val200Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,207,047 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 2 hem. )

Consequence

CASK
NM_001367721.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.230

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant X-41665385-T-C is Benign according to our data. Variant chrX-41665385-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000223 (25/112117) while in subpopulation AFR AF = 0.000712 (22/30891). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 25 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.600A>G	p.Val200Val	synonymous_variant	Exon 7 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.600A>G	p.Val200Val	synonymous_variant	Exon 7 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

112067

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.000658

GnomAD2 exomes

AF:

0.0000608

AC:

AN:

180972

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.000689

Gnomad AMR exome

AF:

0.0000735

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:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1094930

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360404

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

26349

American (AMR)

AF:

0.0000569

AC:

AN:

35137

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19349

East Asian (EAS)

AF:

0.00

AC:

AN:

30175

South Asian (SAS)

AF:

0.00

AC:

AN:

53877

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839435

Other (OTH)

AF:

0.0000217

AC:

AN:

45981

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000223

AC:

AN:

112117

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34295

show subpopulations

African (AFR)

AF:

0.000712

AC:

AN:

30891

American (AMR)

AF:

0.000189

AC:

AN:

10596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3580

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:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53225

Other (OTH)

AF:

0.000649

AC:

AN:

1540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000712

Hom.:

Bravo

AF:

0.000185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CASK: BP4, BP7 -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, CASK-related, X-linked

Benign:1

Dec 02, 2024

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

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.9

(source)

DANN

Benign

0.66

PhyloP100

0.23

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=99/1

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