rs41431245

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001367721.1(CASK):c.363T>C(p.Tyr121=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0041 in 1,148,328 control chromosomes in the GnomAD database, including 71 homozygotes. There are 1,456 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 9 hom., 264 hem., cov: 23)

Exomes 𝑓: 0.0038 ( 62 hom. 1192 hem. )

Consequence

CASK
NM_001367721.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.43

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant X-41739450-A-G is Benign according to our data. Variant chrX-41739450-A-G is described in ClinVar as [Benign]. Clinvar id is 94378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41739450-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.363T>C	p.Tyr121=	synonymous_variant	5/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7 linkuse as main transcript	c.363T>C	p.Tyr121=	synonymous_variant	5/27	5	NM_001367721.1	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.00662

AC:

742

AN:

112021

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

263

AN XY:

34179

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0366

Gnomad SAS

AF:

0.00483

Gnomad FIN

AF:

0.00784

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000788

Gnomad OTH

AF:

0.0146

GnomAD3 exomes

AF:

0.0130

AC:

2365

AN:

182555

Hom.:

AF XY:

0.00976

AC XY:

655

AN XY:

67145

show subpopulations

Gnomad AFR exome

AF:

0.000305

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.000268

Gnomad EAS exome

AF:

0.0394

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00918

Gnomad NFE exome

AF:

0.000772

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00382

AC:

3958

AN:

1036255

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

1192

AN XY:

312817

show subpopulations

Gnomad4 AFR exome

AF:

0.000632

Gnomad4 AMR exome

AF:

0.0562

Gnomad4 ASJ exome

AF:

0.000633

Gnomad4 EAS exome

AF:

0.0317

Gnomad4 SAS exome

AF:

0.00240

Gnomad4 FIN exome

AF:

0.00872

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.00606

GnomAD4 genome

AF:

0.00665

AC:

745

AN:

112073

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

264

AN XY:

34241

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.0435

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0364

Gnomad4 SAS

AF:

0.00484

Gnomad4 FIN

AF:

0.00784

Gnomad4 NFE

AF:

0.000789

Gnomad4 OTH

AF:

0.0144

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Intellectual disability, CASK-related, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

6.8

Dann

Benign

0.52

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