Variant summary

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

The ENST00000378163.7(CASK):c.2442G>A(p.Ala814Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,209,563 control chromosomes in the GnomAD database, including 13 homozygotes. There are 700 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A814A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 27 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 13 hom. 673 hem. )

Consequence

CASK
ENST00000378163.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.919

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-41531085-C-T is Benign according to our data. Variant chrX-41531085-C-T is described in ClinVar as Benign. ClinVar VariationId is 158073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.919 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000527 (59/112057) while in subpopulation SAS AF = 0.0168 (45/2679). AF 95% confidence interval is 0.0129. 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 59 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378163.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASK	NM_001367721.1	MANE Select	c.2442G>A	p.Ala814Ala	synonymous	Exon 25 of 27	NP_001354650.1
CASK	NM_003688.4		c.2427G>A	p.Ala809Ala	synonymous	Exon 25 of 27	NP_003679.2
CASK	NM_001410745.1		c.2424G>A	p.Ala808Ala	synonymous	Exon 24 of 26	NP_001397674.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASK	ENST00000378163.7	TSL:5 MANE Select	c.2442G>A	p.Ala814Ala	synonymous	Exon 25 of 27	ENSP00000367405.1
CASK	ENST00000421587.8	TSL:1	c.2373G>A	p.Ala791Ala	synonymous	Exon 23 of 25	ENSP00000400526.4
CASK	ENST00000378166.9	TSL:1	c.2340G>A	p.Ala780Ala	synonymous	Exon 23 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes

AF:

0.000527

AC:

AN:

112007

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00193

AC:

355

AN:

183505

AF XY:

0.00300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000244

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.00111

AC:

1223

AN:

1097506

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

673

AN XY:

362864

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26382

American (AMR)

AF:

0.0000284

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19379

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30203

South Asian (SAS)

AF:

0.0178

AC:

961

AN:

54129

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000228

AC:

192

AN:

841462

Other (OTH)

AF:

0.00124

AC:

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000527

AC:

AN:

112057

Hom.:

Cov.:

AF XY:

0.000789

AC XY:

AN XY:

34231

show subpopulations

African (AFR)

AF:

0.0000648

AC:

AN:

30869

American (AMR)

AF:

0.00

AC:

AN:

10584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.0168

AC:

AN:

2679

European-Finnish (FIN)

AF:

0.000165

AC:

AN:

6054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

53208

Other (OTH)

AF:

0.00

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000375

Hom.:

Bravo

AF:

0.000234

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CASK-related disorder (1)

Inborn genetic diseases (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.2

(source)

DANN

Benign

0.74

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism (auto)

(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