X-41531460-T-G

Variant names:

• chrX-41531460-T-G
• rs2998250
• NM_001367721.1:c.2318-251A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001367721.1(CASK):​c.2318-251A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 110,711 control chromosomes in the GnomAD database, including 8,677 homozygotes. There are 14,843 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (8677 hom., 14843 hem., cov: 22)
• Consequence: CASK NM_001367721.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.761
• 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), 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-41531460-T-G is Benign according to our data. Variant chrX-41531460-T-G is described in ClinVar as Benign. ClinVar VariationId is 668060.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 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.2318-251A>C		intron	N/A	NP_001354650.1
	CASK	NM_003688.4		c.2303-251A>C		intron	N/A	NP_003679.2
	CASK	NM_001410745.1		c.2300-251A>C		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.2318-251A>C		intron	N/A	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.2249-251A>C		intron	N/A	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.2216-251A>C		intron	N/A	ENSP00000367408.5

Frequencies

GnomAD3 genomes AF: 0.458 AC: 50644 AN: 110659 Hom.: 8669 Cov.: 22

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.458 AC: 50680 AN: 110711 Hom.: 8677 Cov.: 22 AF XY: 0.450 AC XY: 14843 AN XY: 32969

African (AFR) AF: 0.412 AC: 12533 AN: 30402

American (AMR) AF: 0.636 AC: 6621 AN: 10413

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 988 AN: 2642

East Asian (EAS) AF: 0.861 AC: 3018 AN: 3504

South Asian (SAS) AF: 0.615 AC: 1583 AN: 2574

European-Finnish (FIN) AF: 0.320 AC: 1889 AN: 5898

Middle Eastern (MID) AF: 0.400 AC: 86 AN: 215

European-Non Finnish (NFE) AF: 0.433 AC: 22905 AN: 52891

Other (OTH) AF: 0.477 AC: 717 AN: 1504

Alfa AF: 0.446 Hom.: 48167

Bravo AF: 0.485

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.14
DANN	Benign	0.72
PhyloP100		-0.76
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: rs2998250; hg19: chrX-41390713;