rs141840001

chrX-41559798-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001367721.1(CASK):c.1718C>T(p.Thr573Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,209,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T573S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (0 hom. 51 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.55

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CASK
• BP4: Computational evidence support a benign effect (MetaRNN=0.35213417).
• BP6: Variant X-41559798-G-A is Benign according to our data. Variant chrX-41559798-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194841.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000711 (8/112534) while in subpopulation NFE AF= 0.000112 (6/53359). AF 95% confidence interval is 0.0000483. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASK	NM_001367721.1	c.1718C>T	p.Thr573Ile	missense_variant	18/27	ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASK	ENST00000378163.7	c.1718C>T	p.Thr573Ile	missense_variant	18/27	5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.0000711 AC: 8 AN: 112534 Hom.: 0 Cov.: 23 AF XY: 0.0000577 AC XY: 2 AN XY: 34678

Gnomad AFR AF: 0.0000323

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: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000112

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000660 AC: 12 AN: 181937 Hom.: 0 AF XY: 0.000105 AC XY: 7 AN XY: 66467

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: 0.0000538

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 167 AN: 1096581 Hom.: 0 Cov.: 28 AF XY: 0.000141 AC XY: 51 AN XY: 361987

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.0000711 AC: 8 AN: 112534 Hom.: 0 Cov.: 23 AF XY: 0.0000577 AC XY: 2 AN XY: 34678

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.000112

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000212 Hom.: 1

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2016	- -

Intellectual disability, CASK-related, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		0.67	P;B;.;B;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.33, 0.40
MVP		0.81
MPC		1.1
ClinPred		0.21	T
GERP RS		6.0
Varity_R		0.41
gMVP		0.65

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

Other links and lift over

dbSNP: rs141840001; hg19: chrX-41419051;