X-41730577-C-T

Variant names:

• chrX-41730577-C-T
• rs4827286
• NM_001367721.1:c.429+8807G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367721.1(CASK):​c.429+8807G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 110,563 control chromosomes in the GnomAD database, including 5,741 homozygotes. There are 11,935 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (5741 hom., 11935 hem., cov: 22)
• Consequence: CASK NM_001367721.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 2 publications found

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]

CASK Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367721.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.429+8807G>A		intron	N/A	NP_001354650.1
	CASK	NM_003688.4		c.429+8807G>A		intron	N/A	NP_003679.2
	CASK	NM_001410745.1		c.429+8807G>A		intron	N/A	NP_001397674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.429+8807G>A		intron	N/A	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.447+8807G>A		intron	N/A	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.429+8807G>A		intron	N/A	ENSP00000367408.5

Frequencies

GnomAD3 genomes AF: 0.359 AC: 39669 AN: 110509 Hom.: 5743 Cov.: 22

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.385

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.359 AC: 39680 AN: 110563 Hom.: 5741 Cov.: 22 AF XY: 0.364 AC XY: 11935 AN XY: 32789

African (AFR) AF: 0.192 AC: 5842 AN: 30495

American (AMR) AF: 0.547 AC: 5678 AN: 10372

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 901 AN: 2618

East Asian (EAS) AF: 0.860 AC: 3022 AN: 3514

South Asian (SAS) AF: 0.599 AC: 1557 AN: 2599

European-Finnish (FIN) AF: 0.321 AC: 1864 AN: 5803

Middle Eastern (MID) AF: 0.330 AC: 70 AN: 212

European-Non Finnish (NFE) AF: 0.377 AC: 19909 AN: 52768

Other (OTH) AF: 0.388 AC: 587 AN: 1511

Alfa AF: 0.382 Hom.: 23221

Bravo AF: 0.374

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4827286; hg19: chrX-41589830;