X-41520476-C-T

Variant names:

• chrX-41520476-C-T
• NM_001367721.1:c.2725G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367721.1(CASK):​c.2725G>A​(p.Ala909Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.2725G>A	p.Ala909Thr	missense	Exon 27 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2710G>A	p.Ala904Thr	missense	Exon 27 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2707G>A	p.Ala903Thr	missense	Exon 26 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.2725G>A	p.Ala909Thr	missense	Exon 27 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2656G>A	p.Ala886Thr	missense	Exon 25 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2623G>A	p.Ala875Thr	missense	Exon 25 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096582 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54093

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4039

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840819

Other (OTH) AF: 0.00 AC: 0 AN: 46037

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0024	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		0.83	P
Vest4		0.50
MutPred		0.45		Gain of disorder (P = 0.2154)
MVP		0.70
MPC		1.9
ClinPred		0.85	D
GERP RS		5.9
Varity_R		0.69
gMVP		0.67
Mutation Taster		=21/79	disease causing

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

Other links and lift over

hg19: chrX-41379729;