NM_001367721.1:c.846C>G

Variant names:

• chrX-41636647-G-C
• rs886128077
• NM_001367721.1:c.846C>G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001367721.1(CASK):​c.846C>G​(p.Tyr282*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005102807: RT-PCR analysis showed significantly lower levels of CASK expression than her parents and sex- and age-matched control groups (Yang, 2022).". Synonymous variant affecting the same amino acid position (i.e. Y282Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CASK NM_001367721.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.89
• Publications: 1 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

LOC124905180 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005102807: RT-PCR analysis showed significantly lower levels of CASK expression than her parents and sex- and age-matched control groups (Yang, 2022).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41636647-G-C is Pathogenic according to our data. Variant chrX-41636647-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 434588.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.846C>G	p.Tyr282*	stop_gained	Exon 9 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.846C>G	p.Tyr282*	stop_gained	Exon 9 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.846C>G	p.Tyr282*	stop_gained	Exon 9 of 26	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.846C>G	p.Tyr282*	stop_gained	Exon 9 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.864C>G	p.Tyr288*	stop_gained	Exon 9 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.846C>G	p.Tyr282*	stop_gained	Exon 9 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Syndromic X-linked intellectual disability Najm type (2)
1	-	-	FG syndrome 4;C2677903:Syndromic X-linked intellectual disability Najm type;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		1.9
Vest4		0.91
GERP RS		3.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs886128077; hg19: chrX-41495900;