NM_001367721.1:c.2297G>A

Variant names:

Variant summary

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

The NM_001367721.1(CASK):c.2297G>A(p.Arg766Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,205,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R766W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000065 ( 0 hom. 27 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.57

Publications

1 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 (MetaRNN=0.039138973).

BP6

Variant X-41534726-C-T is Benign according to our data. Variant chrX-41534726-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282560.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000512 (57/111347) while in subpopulation AFR AF = 0.00163 (50/30708). AF 95% confidence interval is 0.00127. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 57 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.2297G>A	p.Arg766Gln	missense_variant	Exon 24 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.2297G>A	p.Arg766Gln	missense_variant	Exon 24 of 27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

111295

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

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:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000164

AC:

AN:

183446

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000649

AC:

AN:

1093861

Hom.:

Cov.:

AF XY:

0.0000751

AC XY:

AN XY:

359445

show subpopulations

African (AFR)

AF:

0.00148

AC:

AN:

26329

American (AMR)

AF:

0.000142

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.0000517

AC:

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

30179

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0000239

AC:

AN:

838195

Other (OTH)

AF:

0.000109

AC:

AN:

45945

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000512

AC:

AN:

111347

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

AN XY:

33593

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

30708

American (AMR)

AF:

0.000287

AC:

AN:

10445

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5883

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

53011

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000208

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 29, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 28, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CASK-related disorder

Benign:1

May 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability, CASK-related, X-linked

Benign:1

Dec 24, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.082

MetaRNN

Benign

0.039

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

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

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.23

Sift

Benign

0.047

.;.;.;.;.;D;.;T;.;.;.;.;.;.;.

Sift4G

Benign

0.25

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

Polyphen

0.75

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

Vest4

0.26

MVP

0.86

MPC

1.3

ClinPred

0.046

GERP RS

5.3

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.40

gMVP

0.81

Mutation Taster

=89/11

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