rs137852820

Positions:

• chrX-41589562-G-A
• chrX-41589562-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001367721.1(CASK):​c.1186C>T​(p.Pro396Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,202,665 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 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. P396A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 15 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 9.60

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.

• PP2: Missense variant where missense usually causes diseases, CASK
• BP4: Computational evidence support a benign effect (MetaRNN=0.12711546).
• BP6: Variant X-41589562-G-A is Benign according to our data. Variant chrX-41589562-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11536.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (25/112279) while in subpopulation AFR AF= 0.000809 (25/30900). AF 95% confidence interval is 0.000562. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1	c.1186C>T	p.Pro396Ser	missense_variant	13/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.1186C>T	p.Pro396Ser	missense_variant	13/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 25 AN: 112279 Hom.: 0 Cov.: 23 AF XY: 0.000261 AC XY: 9 AN XY: 34455

Gnomad AFR AF: 0.000809

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 11 AN: 182614 Hom.: 0 AF XY: 0.0000447 AC XY: 3 AN XY: 67134

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000413 AC: 45 AN: 1090386 Hom.: 0 Cov.: 26 AF XY: 0.0000421 AC XY: 15 AN XY: 356230

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000742

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000223 AC: 25 AN: 112279 Hom.: 0 Cov.: 23 AF XY: 0.000261 AC XY: 9 AN XY: 34455

Gnomad4 AFR AF: 0.000809

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000204 Hom.: 1

Bravo AF: 0.000257

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CASK: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2020	This variant is associated with the following publications: (PMID: 19377476, 23871722, 33090494, 24505460, 21954287, 22452838, 19847910, 21735175, 29426960, 25886057, 20029458) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- -

FG syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

This alteration is classified as likely 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. -

Syndromic X-linked intellectual disability Najm type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 06, 2020

This variant, that leads to the substitution of proline in codon 396 for serine, has been previously reported in medical literature to segregate with the phenotype of X-linked intellectual deficiency in one family (PMID: 19377476). However, functional studies demonstrate that it results in a structurally stable protein and interactions with liprin-α, Mint-1 and Veli are preserved (PMID: 24505460). In addition, it is observed at a higher than expected frequency in population databases, including 5 hemizygous individuals (gnomAD v2.1.1). Therefore, this variant was considered to be likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	D
Polyphen		0.0010	B;D;.;B;.;.;.;B;.;.;.;.;.;.
Vest4		0.20, 0.44
MVP		0.88
MPC		1.1
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852820; hg19: chrX-41448815;