rs137852820

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001367721.1(CASK):c.1186C>T(p.Pro396Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,202,665 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 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 0.00022 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 15 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.60

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:

CASK (HGNC:):

CASK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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=0.12711546).

BP6

Variant X-41589562-G-A is Benign according to our data. Variant chrX-41589562-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11536.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (25/112279) while in subpopulation AFR AF= 0.000809 (25/30900). AF 95% confidence interval is 0.000562. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.1186C>T	p.Pro396Ser	missense_variant	13/27	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.1186C>T	p.Pro396Ser	missense_variant	13/27	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

112279

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

AN XY:

34455

show subpopulations

Gnomad AFR

AF:

0.000809

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

182614

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

67134

show subpopulations

Gnomad AFR exome

AF:

0.000685

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000413

AC:

AN:

1090386

Hom.:

Cov.:

AF XY:

0.0000421

AC XY:

AN XY:

356230

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000742

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.000223

AC:

AN:

112279

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

AN XY:

34455

show subpopulations

Gnomad4 AFR

AF:

0.000809

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CASK: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2020	This variant is associated with the following publications: (PMID: 19377476, 23871722, 33090494, 24505460, 21954287, 22452838, 19847910, 21735175, 29426960, 25886057, 20029458) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- -

FG syndrome 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

This alteration is classified as likely 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. -

Syndromic X-linked intellectual disability Najm type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 06, 2020

This variant, that leads to the substitution of proline in codon 396 for serine, has been previously reported in medical literature to segregate with the phenotype of X-linked intellectual deficiency in one family (PMID: 19377476). However, functional studies demonstrate that it results in a structurally stable protein and interactions with liprin-Î±, Mint-1 and Veli are preserved (PMID: 24505460). In addition, it is observed at a higher than expected frequency in population databases, including 5 hemizygous individuals (gnomAD v2.1.1). Therefore, this variant was considered to be likely benign. -

Intellectual disability, CASK-related, X-linked

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.31

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.071

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-0.34

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

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.29

Sift

Benign

0.37

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

Sift4G

Benign

0.81

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

Polyphen

0.0010

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

Vest4

0.20, 0.44

MVP

0.88

MPC

1.1

ClinPred

0.15

GERP RS

5.8

Varity_R

0.11

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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