chrX-41557044-G-A

Position:

chrX-41557044-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001367721.1(CASK):c.1794C>T(p.Asn598=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,206,876 control chromosomes in the GnomAD database, including 2 homozygotes. There are 271 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., 24 hem., cov: 23)

Exomes 𝑓: 0.00059 ( 2 hom. 247 hem. )

Consequence

CASK
NM_001367721.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.56

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=-0.47).

BP6

Variant X-41557044-G-A is Benign according to our data. Variant chrX-41557044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41557044-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000688 (77/111956) while in subpopulation NFE AF= 0.000508 (27/53193). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.1794C>T	p.Asn598=	synonymous_variant	19/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7 linkuse as main transcript	c.1794C>T	p.Asn598=	synonymous_variant	19/27	5	NM_001367721.1	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000688

AC:

AN:

111901

Hom.:

Cov.:

AF XY:

0.000705

AC XY:

AN XY:

34053

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

Gnomad ASJ

AF:

0.00452

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000508

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000993

AC:

182

AN:

183279

Hom.:

AF XY:

0.000944

AC XY:

AN XY:

67765

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00548

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00594

Gnomad NFE exome

AF:

0.000477

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.000593

AC:

649

AN:

1094920

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

247

AN XY:

360448

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00573

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00656

Gnomad4 NFE exome

AF:

0.000287

Gnomad4 OTH exome

AF:

0.000653

GnomAD4 genome

AF:

0.000688

AC:

AN:

111956

Hom.:

Cov.:

AF XY:

0.000703

AC XY:

AN XY:

34118

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00452

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.000508

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000310

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 19, 2016

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2017

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 28, 2018

- -

CASK-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

This variant is classified as likely 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

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.67

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