NM_001367721.1:c.2777A>G

Variant names:

• chrX-41520424-T-C
• rs748918088
• NM_001367721.1:c.2777A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_001367721.1(CASK):​c.2777A>G​(p.Tyr926Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,091,779 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.67
• Publications: 1 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• BP6: Variant X-41520424-T-C is Benign according to our data. Variant chrX-41520424-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 959257.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2777A>G	p.Tyr926Cys	missense	Exon 27 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2762A>G	p.Tyr921Cys	missense	Exon 27 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2759A>G	p.Tyr920Cys	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.2777A>G	p.Tyr926Cys	missense	Exon 27 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.2708A>G	p.Tyr903Cys	missense	Exon 25 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.2675A>G	p.Tyr892Cys	missense	Exon 25 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000554 AC: 1 AN: 180609 AF XY: 0.0000153

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1091779 Hom.: 0 Cov.: 28 AF XY: 0.00000280 AC XY: 1 AN XY: 357681

African (AFR) AF: 0.00 AC: 0 AN: 26294

American (AMR) AF: 0.00 AC: 0 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19333

East Asian (EAS) AF: 0.00 AC: 0 AN: 30147

South Asian (SAS) AF: 0.00 AC: 0 AN: 53923

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40311

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3690

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 837098

Other (OTH) AF: 0.00 AC: 0 AN: 45822

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, CASK-related, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.52		Loss of disorder (P = 0.037)
MVP		0.98
MPC		2.5
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.79
Mutation Taster		=35/65	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: rs748918088; hg19: chrX-41379677;