rs76106850

Variant names:

• chrX-41553836-C-T
• rs76106850
• NM_001367721.1:c.1922G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001367721.1(CASK):​c.1922G>A​(p.Arg641Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,203,462 control chromosomes in the GnomAD database, including 1 homozygotes. There are 74 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R641S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00017 (0 hom. 70 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.75
• Publications: 4 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001367721.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.016835362).
• BP6: Variant X-41553836-C-T is Benign according to our data. Variant chrX-41553836-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166794.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000116 (13/111723) while in subpopulation EAS AF = 0.00308 (11/3576). AF 95% confidence interval is 0.00172. There are 1 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 XL,AD 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.1922G>A	p.Arg641Lys	missense	Exon 21 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.1922G>A	p.Arg641Lys	missense	Exon 21 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.1904G>A	p.Arg635Lys	missense	Exon 20 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.1922G>A	p.Arg641Lys	missense	Exon 21 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.1853G>A	p.Arg618Lys	missense	Exon 19 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.1835G>A	p.Arg612Lys	missense	Exon 19 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111669 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00307

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000224 AC: 41 AN: 183137 AF XY: 0.000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000535

Gnomad EAS exome AF: 0.00231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.000172 AC: 188 AN: 1091739 Hom.: 0 Cov.: 28 AF XY: 0.000196 AC XY: 70 AN XY: 357275

African (AFR) AF: 0.00 AC: 0 AN: 26282

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.000672 AC: 13 AN: 19341

East Asian (EAS) AF: 0.00481 AC: 145 AN: 30164

South Asian (SAS) AF: 0.0000926 AC: 5 AN: 53983

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000598 AC: 5 AN: 836231

Other (OTH) AF: 0.000436 AC: 20 AN: 45911

GnomAD4 genome AF: 0.000116 AC: 13 AN: 111723 Hom.: 1 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33913

African (AFR) AF: 0.00 AC: 0 AN: 30805

American (AMR) AF: 0.00 AC: 0 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2642

East Asian (EAS) AF: 0.00308 AC: 11 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5997

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53144

Other (OTH) AF: 0.000653 AC: 1 AN: 1531

Alfa AF: 0.000100 Hom.: 2

Bravo AF: 0.000136

ExAC AF: 0.000189 AC: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	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	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.83	N
PhyloP100		4.7
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.25	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.50
MutPred		0.53		Gain of methylation at R641 (P = 0.0345)
MVP		0.76
MPC		1.1
ClinPred		0.079	T
GERP RS		6.1
Varity_R		0.28
gMVP		0.87
Mutation Taster		=60/40	polymorphism

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: rs76106850; hg19: chrX-41413089;