Genetic Variant CASK:c.2155+4G>A (chrX-41542687-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001367721.1(CASK):c.2155+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,140,780 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000068 ( 0 hom. 2 hem. )

Consequence

CASK
NM_001367721.1 splice_region, intron

Scores

Splicing: ADA: 0.001976

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.609

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant X-41542687-C-T is Benign according to our data. Variant chrX-41542687-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537751.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1 link	c.2155+4G>A		splice_region_variant, intron_variant	Intron 22 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7 link	c.2155+4G>A		splice_region_variant, intron_variant	Intron 22 of 26	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111765

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33931

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000670

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182524

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67026

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000680

AC:

AN:

1029015

Hom.:

Cov.:

AF XY:

0.00000639

AC XY:

AN XY:

312753

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000528

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000642

Gnomad4 OTH exome

AF:

0.0000228

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111765

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33931

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000670

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CASK-related disorder

Uncertain:1

Jun 16, 2021

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CASK c.2155+4G>A variant is a splice region variant. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is reported at a frequency of 0.000037 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on the available evidence, the c.2155+4G>A variant is classified as a variant of uncertain significance for CASK-related disorders. -

Intellectual disability, CASK-related, X-linked

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0020

dbscSNV1_RF

Benign

0.056

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