rs587783359

Positions:

• chrX-41542815-T-C
• chrX-41542815-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367721.1(CASK):​c.2040-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,019,577 control chromosomes in the GnomAD database, including 11 homozygotes. There are 310 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 0.0056 (5 hom., 156 hem., cov: 23)
  • Exomes 𝑓: 0.00070 (6 hom. 154 hem.)
• Consequence: CASK NM_001367721.1 intron
• Scores: Splicing: ADA: 0.00002441
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.30

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-41542815-T-C is Benign according to our data. Variant chrX-41542815-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41542815-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00556 (623/111980) while in subpopulation AFR AF= 0.0192 (594/30882). AF 95% confidence interval is 0.018. There are 5 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1	c.2040-9A>G		intron_variant		ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.2040-9A>G		intron_variant		5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 619 AN: 111925 Hom.: 5 Cov.: 23 AF XY: 0.00446 AC XY: 152 AN XY: 34105

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00596

GnomAD3 exomes AF: 0.00159 AC: 282 AN: 176894 Hom.: 2 AF XY: 0.000950 AC XY: 59 AN XY: 62130

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000704 AC: 639 AN: 907597 Hom.: 6 Cov.: 18 AF XY: 0.000639 AC XY: 154 AN XY: 241015

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.000553

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000828

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000223

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00556 AC: 623 AN: 111980 Hom.: 5 Cov.: 23 AF XY: 0.00457 AC XY: 156 AN XY: 34170

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00588

Alfa AF: 0.00243 Hom.: 9

Bravo AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Intellectual disability, CASK-related, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs138290714; hg19: chrX-41402068;