Variant X-41520458-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001367721.1(CASK):c.2743A>G(p.Thr915Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,096,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000073 ( 0 hom. 2 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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 links:

CASK-AS1 (HGNC:40126): (CASK antisense RNA 1)

CASK-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASK. . Gene score misZ 4.2502 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic X-linked intellectual disability Najm type, X-linked syndromic intellectual disability, developmental and epileptic encephalopathy, FG syndrome 4.

BP4

Computational evidence support a benign effect (MetaRNN=0.17808211).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1 linkuse as main transcript	c.2743A>G	p.Thr915Ala	missense_variant	27/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7 linkuse as main transcript	c.2743A>G	p.Thr915Ala	missense_variant	27/27	5	NM_001367721.1	A1	O14936-1
CASK-AS1	ENST00000451126.1 linkuse as main transcript	n.331+92T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182790

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67250

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000729

AC:

AN:

1096722

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

362146

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000595

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.39

.;.;.;.;.;.;.;T;.;.;.;.;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;.;.;.;.;.;L;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.3

.;.;.;.;.;N;.;N;.;.;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.23

.;.;.;.;.;T;.;T;.;.;.;.;.;.

Sift4G

Benign

0.27

.;.;.;.;.;T;.;T;.;.;.;.;.;.

Polyphen

0.13

B;P;.;B;.;B;.;B;.;.;.;.;.;.

Vest4

0.43

MutPred

0.33

.;.;.;.;.;.;.;Loss of solvent accessibility (P = 0.3744);.;.;.;.;.;.;

MVP

0.79

MPC

1.0

ClinPred

0.11

GERP RS

5.8

Varity_R

0.27

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over