X-41714313-T-C

Variant names:

• chrX-41714313-T-C
• rs6609159
• NM_001367721.1:c.429+25071A>G

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+25071A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 110,170 control chromosomes in the GnomAD database, including 9,630 homozygotes. There are 15,669 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 0.49 (9630 hom., 15669 hem., cov: 22)
• Consequence: CASK NM_001367721.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 3 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), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.429+25071A>G		intron	N/A	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.429+25071A>G		intron	N/A	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.429+25071A>G		intron	N/A	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.429+25071A>G		intron	N/A	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.447+25071A>G		intron	N/A	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.429+25071A>G		intron	N/A	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.487 AC: 53668 AN: 110117 Hom.: 9625 Cov.: 22

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.435

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.496

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

GnomAD4 genome AF: 0.487 AC: 53704 AN: 110170 Hom.: 9630 Cov.: 22 AF XY: 0.482 AC XY: 15669 AN XY: 32476

African (AFR) AF: 0.460 AC: 13909 AN: 30266

American (AMR) AF: 0.644 AC: 6682 AN: 10382

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1020 AN: 2632

East Asian (EAS) AF: 0.865 AC: 3020 AN: 3493

South Asian (SAS) AF: 0.639 AC: 1638 AN: 2565

European-Finnish (FIN) AF: 0.366 AC: 2114 AN: 5774

Middle Eastern (MID) AF: 0.425 AC: 90 AN: 212

European-Non Finnish (NFE) AF: 0.458 AC: 24149 AN: 52682

Other (OTH) AF: 0.497 AC: 746 AN: 1500

Alfa AF: 0.483 Hom.: 45805

Bravo AF: 0.512

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.52
PhyloP100		-2.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6609159;

hg19: chrX-41573566;