rs1555975458

Variant names:

• chrX-41534705-C-T
• rs1555975458
• NM_001367721.1:c.2317+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_001367721.1(CASK):​c.2317+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006486510: RNA studies have demonstrated that this alteration results in abnormal splicing (Cristofoli, 2018).".

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CASK NM_001367721.1 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029126214 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV006486510: RNA studies have demonstrated that this alteration results in abnormal splicing (Cristofoli, 2018).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41534705-C-T is Pathogenic according to our data. Variant chrX-41534705-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367721.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.2317+1G>A		splice_donor intron	N/A	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2302+1G>A		splice_donor intron	N/A	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2299+1G>A		splice_donor intron	N/A	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.2317+1G>A		splice_donor intron	N/A	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2248+1G>A		splice_donor intron	N/A	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2215+1G>A		splice_donor intron	N/A	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1076922 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 345190

African (AFR) AF: 0.00 AC: 0 AN: 25991

American (AMR) AF: 0.00 AC: 0 AN: 35169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19257

East Asian (EAS) AF: 0.00 AC: 0 AN: 30112

South Asian (SAS) AF: 0.00 AC: 0 AN: 53630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 822832

Other (OTH) AF: 0.00 AC: 0 AN: 45350

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability, CASK-related, X-linked (1)
1	-	-	not provided (1)
1	-	-	Syndromic X-linked intellectual disability Najm type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.6
GERP RS		5.3
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555975458; hg19: chrX-41393958; COSMIC: COSV59377601; COSMIC: COSV59377601;