NM_001367721.1:c.1186C>T

Variant names:

• chrX-41589562-G-A
• rs137852820
• NM_001367721.1:c.1186C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001367721.1(CASK):​c.1186C>T​(p.Pro396Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,202,665 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 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. P396A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 15 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 9.60
• Publications: 11 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 Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12711546).
• BP6: Variant X-41589562-G-A is Benign according to our data. Variant chrX-41589562-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11536.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000223 (25/112279) while in subpopulation AFR AF = 0.000809 (25/30900). AF 95% confidence interval is 0.000562. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 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.1186C>T	p.Pro396Ser	missense	Exon 13 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.1186C>T	p.Pro396Ser	missense	Exon 13 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.1168C>T	p.Pro390Ser	missense	Exon 12 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.1186C>T	p.Pro396Ser	missense	Exon 13 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.1186C>T	p.Pro396Ser	missense	Exon 12 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.1168C>T	p.Pro390Ser	missense	Exon 12 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 25 AN: 112279 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000809

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: 0.00

GnomAD2 exomes AF: 0.0000602 AC: 11 AN: 182614 AF XY: 0.0000447

Gnomad AFR exome AF: 0.000685

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000413 AC: 45 AN: 1090386 Hom.: 0 Cov.: 26 AF XY: 0.0000421 AC XY: 15 AN XY: 356230

African (AFR) AF: 0.00122 AC: 32 AN: 26262

American (AMR) AF: 0.00 AC: 0 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 30125

South Asian (SAS) AF: 0.0000742 AC: 4 AN: 53890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40480

Middle Eastern (MID) AF: 0.000503 AC: 2 AN: 3978

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835290

Other (OTH) AF: 0.000153 AC: 7 AN: 45839

GnomAD4 genome AF: 0.000223 AC: 25 AN: 112279 Hom.: 0 Cov.: 23 AF XY: 0.000261 AC XY: 9 AN XY: 34455

African (AFR) AF: 0.000809 AC: 25 AN: 30900

American (AMR) AF: 0.00 AC: 0 AN: 10563

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3621

South Asian (SAS) AF: 0.00 AC: 0 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53292

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.000443 Hom.: 3

Bravo AF: 0.000257

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
1	-	-	FG syndrome 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, CASK-related, X-linked (1)
-	-	1	Syndromic X-linked intellectual disability Najm type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.34	N
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.29
Sift	Benign	0.37	T
Sift4G	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.88
MPC		1.1
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.69
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852820; hg19: chrX-41448815;