Genetic Variant NM_001367721.1:c.83G>T (chrX-41853204-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001367721.1(CASK):c.83G>T(p.Arg28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.48

Publications

18 publications found

Variant links:

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

CASK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

PP5

Variant X-41853204-C-A is Pathogenic according to our data. Variant chrX-41853204-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11532.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASK	NM_001367721.1	MANE Select	c.83G>T	p.Arg28Leu	missense	Exon 2 of 27	NP_001354650.1
CASK	NM_003688.4		c.83G>T	p.Arg28Leu	missense	Exon 2 of 27	NP_003679.2
CASK	NM_001410745.1		c.83G>T	p.Arg28Leu	missense	Exon 2 of 26	NP_001397674.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASK	ENST00000378163.7	TSL:5 MANE Select	c.83G>T	p.Arg28Leu	missense	Exon 2 of 27	ENSP00000367405.1
CASK	ENST00000421587.8	TSL:1	c.83G>T	p.Arg28Leu	missense	Exon 2 of 25	ENSP00000400526.4
CASK	ENST00000378166.9	TSL:1	c.83G>T	p.Arg28Leu	missense	Exon 2 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FG syndrome 4

Pathogenic:1

Feb 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.35

PhyloP100

7.5

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.48

Sift

Benign

0.13

Sift4G

Uncertain

0.023

Polyphen

0.99

Vest4

0.86

MutPred

0.79

Loss of MoRF binding (P = 0.0447)

MVP

0.92

MPC

2.5

ClinPred

0.94

GERP RS

5.4

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.85

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over