rs966502877

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001367721.1(CASK):c.2588C>T(p.Thr863Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,192,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T863T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.21

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), G2P, Ambry Genetics
syndromic X-linked intellectual disability Najm type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
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 -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000462 (5/1082916) while in subpopulation AMR AF = 0.000114 (4/35020). AF 95% confidence interval is 0.0000386. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 5 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	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	NM_001367721.1	MANE Select	c.2588C>T	p.Thr863Ile	missense	Exon 26 of 27	NP_001354650.1	O14936-1
CASK	NM_003688.4		c.2573C>T	p.Thr858Ile	missense	Exon 26 of 27	NP_003679.2	O14936-2
CASK	NM_001410745.1		c.2570C>T	p.Thr857Ile	missense	Exon 25 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	ENST00000378163.7	TSL:5 MANE Select	c.2588C>T	p.Thr863Ile	missense	Exon 26 of 27	ENSP00000367405.1	O14936-1
CASK	ENST00000421587.8	TSL:1	c.2519C>T	p.Thr840Ile	missense	Exon 24 of 25	ENSP00000400526.4	A0A7I2RJN6
CASK	ENST00000378166.9	TSL:1	c.2486C>T	p.Thr829Ile	missense	Exon 24 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes

AF:

0.00000910

AC:

AN:

109840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000968

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:

0.00

GnomAD2 exomes

AF:

0.0000226

AC:

AN:

176655

AF XY:

0.0000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000148

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:

0.00000462

AC:

AN:

1082916

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26157

American (AMR)

AF:

0.000114

AC:

AN:

35020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19190

East Asian (EAS)

AF:

0.00

AC:

AN:

30073

South Asian (SAS)

AF:

0.0000188

AC:

AN:

53297

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829243

Other (OTH)

AF:

0.00

AC:

AN:

45556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000910

AC:

AN:

109840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30033

American (AMR)

AF:

0.0000968

AC:

AN:

10328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52812

Other (OTH)

AF:

0.00

AC:

AN:

1463

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

9.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.35

Sift

Benign

0.084

Sift4G

Benign

0.15

Polyphen

0.95

Vest4

0.55

MutPred

0.48

Loss of glycosylation at T863 (P = 0.0303)

MVP

0.79

MPC

1.1

ClinPred

0.33

GERP RS

4.7

Varity_R

0.58

gMVP

0.73

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over