rs76106850

chrX-41553836-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 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). Synonymous variant affecting the same amino acid position (i.e. R641R) has been classified as Likely benign.

• 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

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 -10 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, 5 uncertain in NM_001367721.1
• PP2: Missense variant where missense usually causes diseases, CASK
• 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 id is 166794.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1	c.1922G>A	p.Arg641Lys	missense_variant	21/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.1922G>A	p.Arg641Lys	missense_variant	21/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111669 Hom.: 1 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33849

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

GnomAD3 exomes AF: 0.000224 AC: 41 AN: 183137 Hom.: 1 AF XY: 0.000251 AC XY: 17 AN XY: 67623

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000672

Gnomad4 EAS exome AF: 0.00481

Gnomad4 SAS exome AF: 0.0000926

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000598

Gnomad4 OTH exome AF: 0.000436

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000653

Alfa AF: 0.000211 Hom.: 2

Bravo AF: 0.000136

ExAC AF: 0.000189 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2020	This variant is associated with the following publications: (PMID: 31139143) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CASK: PP2, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
Polyphen		0.0040	B;B;.;B;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.50
MutPred		0.53		.;.;.;Gain of methylation at R641 (P = 0.0345);.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs76106850; hg19: chrX-41413089;