chrX-41712121-C-T

Variant names:

• chrX-41712121-C-T
• rs2104686
• NM_001367721.1:c.429+27263G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367721.1(CASK):​c.429+27263G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.80 (25421 hom., 25904 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: CASK NM_001367721.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.429+27263G>A		intron_variant	Intron 5 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.429+27263G>A		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes AF: 0.803 AC: 88528 AN: 110191 Hom.: 25421 Cov.: 22

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.716

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.785

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

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.803 AC: 88566 AN: 110245 Hom.: 25421 Cov.: 22 AF XY: 0.798 AC XY: 25904 AN XY: 32475

African (AFR) AF: 0.861 AC: 26099 AN: 30314

American (AMR) AF: 0.846 AC: 8863 AN: 10471

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 1807 AN: 2625

East Asian (EAS) AF: 0.991 AC: 3438 AN: 3468

South Asian (SAS) AF: 0.856 AC: 2203 AN: 2574

European-Finnish (FIN) AF: 0.660 AC: 3796 AN: 5753

Middle Eastern (MID) AF: 0.693 AC: 149 AN: 215

European-Non Finnish (NFE) AF: 0.768 AC: 40445 AN: 52643

Other (OTH) AF: 0.789 AC: 1182 AN: 1499

Alfa AF: 0.785 Hom.: 7722

Bravo AF: 0.821

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.94
DANN	Benign	0.82
PhyloP100		-2.3
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: rs2104686; hg19: chrX-41571374;