rs369792621

Variant names:

• chrX-41531057-G-A
• rs369792621
• NM_001367721.1:c.2470C>T
• CASK p.Arg824Trp

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_001367721.1(CASK):​c.2470C>T​(p.Arg824Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000479 in 1,209,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R824Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000049 (0 hom. 18 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.36
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• BP6: Variant X-41531057-G-A is Benign according to our data. Variant chrX-41531057-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 590126.
• BS2: High AC in GnomAdExome4 at 54 AD,XL gene.

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.2470C>T	p.Arg824Trp	missense	Exon 25 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2455C>T	p.Arg819Trp	missense	Exon 25 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2452C>T	p.Arg818Trp	missense	Exon 24 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.2470C>T	p.Arg824Trp	missense	Exon 25 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2401C>T	p.Arg801Trp	missense	Exon 23 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2368C>T	p.Arg790Trp	missense	Exon 23 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 111960 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183463 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000492 AC: 54 AN: 1097952 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 18 AN XY: 363308

African (AFR) AF: 0.0000758 AC: 2 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000487 AC: 41 AN: 841868

Other (OTH) AF: 0.000152 AC: 7 AN: 46088

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 111960 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34130

African (AFR) AF: 0.0000650 AC: 2 AN: 30789

American (AMR) AF: 0.00 AC: 0 AN: 10572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6035

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53208

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, CASK-related, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.98
gMVP		0.86
Mutation Taster		=5/95	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs369792621;

hg19: chrX-41390310;

COSMIC: COSV59363352;

COSMIC: COSV59363352;