rs1292052935

Variant names:

• chrX-41520434-A-T
• rs1292052935
• NM_001367721.1:c.2767T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001367721.1(CASK):​c.2767T>A​(p.Ser923Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000731 in 1,094,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 XL,AD gene.

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.2767T>A	p.Ser923Thr	missense	Exon 27 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2752T>A	p.Ser918Thr	missense	Exon 27 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2749T>A	p.Ser917Thr	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.2767T>A	p.Ser923Thr	missense	Exon 27 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2698T>A	p.Ser900Thr	missense	Exon 25 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2665T>A	p.Ser889Thr	missense	Exon 25 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181637 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000731 AC: 8 AN: 1094452 Hom.: 0 Cov.: 28 AF XY: 0.00000555 AC XY: 2 AN XY: 360074

African (AFR) AF: 0.00 AC: 0 AN: 26337

American (AMR) AF: 0.0000284 AC: 1 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30166

South Asian (SAS) AF: 0.00 AC: 0 AN: 54013

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40369

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3838

European-Non Finnish (NFE) AF: 0.00000834 AC: 7 AN: 839250

Other (OTH) AF: 0.00 AC: 0 AN: 45925

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, CASK-related, X-linked (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.98	D
Vest4		0.46
MutPred		0.42		Loss of disorder (P = 0.0306)
MVP		0.90
MPC		1.5
ClinPred		0.49	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.64
Mutation Taster		=44/56	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

dbSNP: rs1292052935; hg19: chrX-41379687;