NM_001367721.1:c.2588C>T

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), 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.2588C>T	p.Thr863Ile	missense_variant	Exon 26 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.2588C>T	p.Thr863Ile	missense_variant	Exon 26 of 27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, CASK-related, X-linked

Uncertain:1

Jul 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 858 of the CASK protein (p.Thr858Ile). This variant is present in population databases (no rsID available, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CASK protein function. ClinVar contains an entry for this variant (Variation ID: 470210). This variant has not been reported in the literature in individuals affected with CASK-related conditions. -

Computational scores

Source: dbNSFP v4.3

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

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

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.46

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;.;.;.;.;.;.;L;.;.;.;.;.;.

PhyloP100

9.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.1

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

REVEL

Uncertain

0.35

Sift

Benign

0.084

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

Sift4G

Benign

0.15

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

Polyphen

0.95

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

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over