rs147738759

chrX-41665385-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001367721.1(CASK):c.600A>G(p.Val200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,207,047 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 0.00022 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 2 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.230

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-41665385-T-C is Benign according to our data. Variant chrX-41665385-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (25/112117) while in subpopulation AFR AF= 0.000712 (22/30891). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. 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.600A>G	p.Val200=	synonymous_variant	7/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.600A>G	p.Val200=	synonymous_variant	7/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 112067 Hom.: 0 Cov.: 22 AF XY: 0.000117 AC XY: 4 AN XY: 34235

Gnomad AFR AF: 0.000681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.000658

GnomAD3 exomes AF: 0.0000608 AC: 11 AN: 180972 Hom.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65604

Gnomad AFR exome AF: 0.000689

Gnomad AMR exome AF: 0.0000735

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1094930 Hom.: 0 Cov.: 29 AF XY: 0.00000555 AC XY: 2 AN XY: 360404

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.000223 AC: 25 AN: 112117 Hom.: 0 Cov.: 22 AF XY: 0.000146 AC XY: 5 AN XY: 34295

Gnomad4 AFR AF: 0.000712

Gnomad4 AMR AF: 0.000189

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: 0.000649

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

CASK: BP4, BP7 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.9
Dann	Benign	0.66

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: rs147738759; hg19: chrX-41524638;