rs73470569

Positions:

• chrX-41610031-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367721.1(CASK):​c.1034-6C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009656
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.827

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CASK	NM_001367721.1	c.1034-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.1034-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001367721.1	ENSP00000367405	A1

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 9472 AN: 111337 Hom.: 1047 Cov.: 23 AF XY: 0.0758 AC XY: 2546 AN XY: 33567

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

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.: 29 AF XY: 0.00743 AC XY: 2685 AN XY: 361159

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.: 23 AF XY: 0.0760 AC XY: 2555 AN XY: 33632

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

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	-0.71
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

Other links and lift over

dbSNP: rs73470569; hg19: chrX-41469284;