rs143991107

Positions:

• chrX-41557044-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367721.1(CASK):​c.1794C>T​(p.Asn598=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,206,876 control chromosomes in the GnomAD database, including 2 homozygotes. There are 271 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00059 (2 hom. 247 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.56

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-41557044-G-A is Benign according to our data. Variant chrX-41557044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41557044-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000688 (77/111956) while in subpopulation NFE AF= 0.000508 (27/53193). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1	c.1794C>T	p.Asn598=	synonymous_variant	19/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.1794C>T	p.Asn598=	synonymous_variant	19/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.000688 AC: 77 AN: 111901 Hom.: 0 Cov.: 23 AF XY: 0.000705 AC XY: 24 AN XY: 34053

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000508

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000993 AC: 182 AN: 183279 Hom.: 1 AF XY: 0.000944 AC XY: 64 AN XY: 67765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00594

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000593 AC: 649 AN: 1094920 Hom.: 2 Cov.: 28 AF XY: 0.000685 AC XY: 247 AN XY: 360448

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00573

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00656

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.000688 AC: 77 AN: 111956 Hom.: 0 Cov.: 23 AF XY: 0.000703 AC XY: 24 AN XY: 34118

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000951

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.000508

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00127 Hom.: 9

Bravo AF: 0.000310

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 19, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2017

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2018

- -

CASK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.67

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: rs143991107; hg19: chrX-41416297;