Variant rs759074946 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP2PP3BP6_ModerateBS2

The NM_001367721.1(CASK):c.2227G>C(p.Val743Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,186,810 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000028 ( 0 hom. 10 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.57

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASK. . Gene score misZ 4.2502 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic X-linked intellectual disability Najm type, X-linked syndromic intellectual disability, developmental and epileptic encephalopathy, FG syndrome 4.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

BP6

Variant X-41534902-C-G is Benign according to our data. Variant chrX-41534902-C-G is described in ClinVar as [Benign]. Clinvar id is 580046.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.2227G>C	p.Val743Leu	missense_variant	23/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7 linkuse as main transcript	c.2227G>C	p.Val743Leu	missense_variant	23/27	5	NM_001367721.1	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112323

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34471

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

180859

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65457

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000279

AC:

AN:

1074487

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

341995

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000329

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112323

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34471

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, CASK-related, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.76

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

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.5

.;.;.;.;.;.;.;M;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.8

.;.;.;.;.;D;.;D;.;.;.;.;.;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

.;.;.;.;.;D;.;D;.;.;.;.;.;.;.

Sift4G

Uncertain

0.0040

.;.;.;.;.;D;.;D;.;.;.;.;.;.;.

Polyphen

1.0

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

Vest4

0.76

MutPred

0.61

.;.;.;.;.;.;.;Loss of methylation at K740 (P = 0.0669);.;.;.;.;.;.;.;

MVP

0.88

MPC

2.1

ClinPred

0.87

GERP RS

5.4

Varity_R

0.93

gMVP

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over