Genetic Variant NM_001367721.1:c.316C>T (chrX-41745564-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001367721.1(CASK):c.316C>T(p.Arg106*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CASK
NM_001367721.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.30

Publications

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-41745564-G-A is Pathogenic according to our data. Variant chrX-41745564-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	UniProt
CASK	NM_001367721.1	MANE Select	c.316C>T	p.Arg106*	stop_gained	Exon 4 of 27	NP_001354650.1	O14936-1
CASK	NM_003688.4		c.316C>T	p.Arg106*	stop_gained	Exon 4 of 27	NP_003679.2	O14936-2
CASK	NM_001410745.1		c.316C>T	p.Arg106*	stop_gained	Exon 4 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	ENST00000378163.7	TSL:5 MANE Select	c.316C>T	p.Arg106*	stop_gained	Exon 4 of 27	ENSP00000367405.1	O14936-1
CASK	ENST00000421587.8	TSL:1	c.334C>T	p.Arg112*	stop_gained	Exon 4 of 25	ENSP00000400526.4	A0A7I2RJN6
CASK	ENST00000378166.9	TSL:1	c.316C>T	p.Arg106*	stop_gained	Exon 4 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091271

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357009

African (AFR)

AF:

0.00

AC:

AN:

26267

American (AMR)

AF:

0.00

AC:

AN:

35187

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19339

East Asian (EAS)

AF:

0.00

AC:

AN:

30149

South Asian (SAS)

AF:

0.00

AC:

AN:

53805

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836044

Other (OTH)

AF:

0.00

AC:

AN:

45874

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Syndromic X-linked intellectual disability Najm type (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.85

PhyloP100

3.3

Vest4

0.93

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over