rs371990384

chrX-41531094-G-A

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.2433C>T(p.His811=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,208,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 106 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 0.00011 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00030 (0 hom. 103 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.135

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=-0.7).
• BP6: Variant X-41531094-G-A is Benign according to our data. Variant chrX-41531094-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 388002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41531094-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.135 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000107 (12/112032) while in subpopulation NFE AF= 0.000169 (9/53210). AF 95% confidence interval is 0.0000873. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1	c.2433C>T	p.His811=	synonymous_variant	25/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.2433C>T	p.His811=	synonymous_variant	25/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 111979 Hom.: 0 Cov.: 23 AF XY: 0.0000879 AC XY: 3 AN XY: 34145

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

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: 0.000169

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 22 AN: 183512 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000295 AC: 324 AN: 1096586 Hom.: 0 Cov.: 31 AF XY: 0.000285 AC XY: 103 AN XY: 361954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000363

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112032 Hom.: 0 Cov.: 23 AF XY: 0.0000877 AC XY: 3 AN XY: 34208

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 3

Bravo AF: 0.000113

EpiCase AF: 0.000382

EpiControl AF: 0.000296

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

Dec 02, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.29
Dann	Benign	0.54

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: rs371990384; hg19: chrX-41390347; COSMIC: COSV100587253; COSMIC: COSV100587253;