NM_001367721.1:c.1034-6C>T

Variant names:

Variant summary

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

The NM_001367721.1(CASK):c.1034-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,207,117 control chromosomes in the GnomAD database, including 2,092 homozygotes. There are 5,240 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 1048 hom., 2555 hem., cov: 23)

Exomes 𝑓: 0.0094 ( 1044 hom. 2685 hem. )

Consequence

CASK
NM_001367721.1 splice_region, intron

Scores

Splicing: ADA: 0.00009656

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.827

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant X-41610031-G-A is Benign according to our data. Variant chrX-41610031-G-A is described in ClinVar as [Benign]. Clinvar id is 94374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41610031-G-A is described in Lovd as [Benign]. Variant chrX-41610031-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.1034-6C>T		splice_region_variant, intron_variant	Intron 11 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7 link	c.1034-6C>T		splice_region_variant, intron_variant	Intron 11 of 26	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.0851

AC:

9472

AN:

111337

Hom.:

1047

Cov.:

AF XY:

0.0758

AC XY:

2546

AN XY:

33567

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00225

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.000828

Gnomad OTH

AF:

0.0537

GnomAD3 exomes

AF:

0.0247

AC:

4444

AN:

179855

Hom.:

490

AF XY:

0.0153

AC XY:

987

AN XY:

64493

show subpopulations

Gnomad AFR exome

AF:

0.305

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000810

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000576

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.00936

AC:

10255

AN:

1095725

Hom.:

1044

Cov.:

AF XY:

0.00743

AC XY:

2685

AN XY:

361159

show subpopulations

Gnomad4 AFR exome

AF:

0.314

Gnomad4 AMR exome

AF:

0.0169

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000910

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000397

Gnomad4 OTH exome

AF:

0.0207

GnomAD4 genome

AF:

0.0851

AC:

9482

AN:

111392

Hom.:

1048

Cov.:

AF XY:

0.0760

AC XY:

2555

AN XY:

33632

show subpopulations

Gnomad4 AFR

AF:

0.298

Gnomad4 AMR

AF:

0.0265

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00150

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000828

Gnomad4 OTH

AF:

0.0531

Alfa

AF:

0.0452

Hom.:

303

Bravo

AF:

0.0987

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 14, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability, CASK-related, X-linked

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.9

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000097

dbscSNV1_RF

Benign

0.0060

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