rs76106850

Positions:

chrX-41553836-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001367721.1(CASK):c.1922G>A(p.Arg641Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,203,462 control chromosomes in the GnomAD database, including 1 homozygotes. There are 74 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).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 70 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.75

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 Benign. Variant got -12 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.016835362).

BP6

Variant X-41553836-C-T is Benign according to our data. Variant chrX-41553836-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166794.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000116 (13/111723) while in subpopulation EAS AF= 0.00308 (11/3576). AF 95% confidence interval is 0.00172. There are 1 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.1922G>A	p.Arg641Lys	missense_variant	21/27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7 linkuse as main transcript	c.1922G>A	p.Arg641Lys	missense_variant	21/27	5	NM_001367721.1	ENSP00000367405	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

111669

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33849

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000379

Gnomad EAS

AF:

0.00307

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.000224

AC:

AN:

183137

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

67623

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000535

Gnomad EAS exome

AF:

0.00231

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000884

GnomAD4 exome

AF:

0.000172

AC:

188

AN:

1091739

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

357275

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000672

Gnomad4 EAS exome

AF:

0.00481

Gnomad4 SAS exome

AF:

0.0000926

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000598

Gnomad4 OTH exome

AF:

0.000436

GnomAD4 genome

AF:

0.000116

AC:

AN:

111723

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33913

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000379

Gnomad4 EAS

AF:

0.00308

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000653

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2020	This variant is associated with the following publications: (PMID: 31139143) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CASK: PP2, BS1, BS2 -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2018

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. -

Intellectual disability, CASK-related, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Benign

0.85

DEOGEN2

Benign

0.13

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

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.017

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.83

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

0.25

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

REVEL

Benign

0.23

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0040

B;B;.;B;.;B;.;B;.;.;.;.;.;.;.

Vest4

0.50

MutPred

0.53

.;.;.;Gain of methylation at R641 (P = 0.0345);.;.;.;Gain of methylation at R641 (P = 0.0345);.;.;.;.;.;.;.;

MVP

0.76

MPC

1.1

ClinPred

0.079

GERP RS

6.1

Varity_R

0.28

gMVP

0.87

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

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