rs375004542

Positions:

• chrX-41578538-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001367721.1(CASK):​c.1315-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 1,149,955 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000077 (0 hom. 33 hem.)
• Consequence: CASK NM_001367721.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003751
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.11

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-41578538-T-C is Benign according to our data. Variant chrX-41578538-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000894 (10/111854) while in subpopulation SAS AF= 0.000754 (2/2653). AF 95% confidence interval is 0.000134. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASK	NM_001367721.1	c.1315-10A>G		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.1315-10A>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001367721.1	ENSP00000367405	A1

Frequencies

GnomAD3 genomes AF: 0.0000894 AC: 10 AN: 111798 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 33972

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000753

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000752

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00851

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000856 AC: 15 AN: 175280 Hom.: 0 AF XY: 0.000116 AC XY: 7 AN XY: 60360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000377

Gnomad ASJ exome AF: 0.000552

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.0000771 AC: 80 AN: 1038101 Hom.: 0 Cov.: 24 AF XY: 0.000106 AC XY: 33 AN XY: 310129

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000578

Gnomad4 ASJ exome AF: 0.000475

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000291

Gnomad4 OTH exome AF: 0.000204

GnomAD4 genome AF: 0.0000894 AC: 10 AN: 111854 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 34038

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000753

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000754

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 13, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.062
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: rs375004542; hg19: chrX-41437791;