rs141158465

Positions:

chrX-41531085-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001367721.1(CASK):c.2442G>A(p.Ala814=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,209,563 control chromosomes in the GnomAD database, including 13 homozygotes. There are 700 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 27 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 13 hom. 673 hem. )

Consequence

CASK
NM_001367721.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.919

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-41531085-C-T is Benign according to our data. Variant chrX-41531085-C-T is described in ClinVar as [Benign]. Clinvar id is 158073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.919 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000527 (59/112057) while in subpopulation SAS AF= 0.0168 (45/2679). AF 95% confidence interval is 0.0129. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.2442G>A	p.Ala814=	synonymous_variant	25/27	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.2442G>A	p.Ala814=	synonymous_variant	25/27	5	NM_001367721.1	ENSP00000367405	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000527

AC:

AN:

112007

Hom.:

Cov.:

AF XY:

0.000790

AC XY:

AN XY:

34171

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00193

AC:

355

AN:

183505

Hom.:

AF XY:

0.00300

AC XY:

204

AN XY:

67937

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad SAS exome

AF:

0.0170

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000244

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.00111

AC:

1223

AN:

1097506

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

673

AN XY:

362864

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.0178

Gnomad4 FIN exome

AF:

0.000173

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000527

AC:

AN:

112057

Hom.:

Cov.:

AF XY:

0.000789

AC XY:

AN XY:

34231

show subpopulations

Gnomad4 AFR

AF:

0.0000648

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.000165

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000564

Hom.:

Bravo

AF:

0.000234

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 11, 2017

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 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

Aug 01, 2018

- -

CASK-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.2

DANN

Benign

0.74

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