NM_001367721.1:c.1717A>G

Variant names:

• chrX-41559799-T-C
• rs900079494
• NM_001367721.1:c.1717A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367721.1(CASK):​c.1717A>G​(p.Thr573Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,528 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T573I) has been classified 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: Not reported in ClinVar
• Conservation: PhyloP100: 4.82
• 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 Gene-Disease associations (from GenCC):

• FG syndrome 4

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

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18640432).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.1717A>G	p.Thr573Ala	missense	Exon 18 of 27	NP_001354650.1
	CASK	NM_003688.4		c.1717A>G	p.Thr573Ala	missense	Exon 18 of 27	NP_003679.2
	CASK	NM_001410745.1		c.1699A>G	p.Thr567Ala	missense	Exon 17 of 26	NP_001397674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.1717A>G	p.Thr573Ala	missense	Exon 18 of 27	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.1717A>G	p.Thr573Ala	missense	Exon 17 of 25	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.1699A>G	p.Thr567Ala	missense	Exon 17 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181859 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: 0.00000182 AC: 2 AN: 1096528 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 1 AN XY: 361930

African (AFR) AF: 0.0000379 AC: 1 AN: 26382

American (AMR) AF: 0.0000284 AC: 1 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 53902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840817

Other (OTH) AF: 0.00 AC: 0 AN: 46033

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.12
Sift	Uncertain	0.028	D
Sift4G	Benign	0.23	T
Polyphen		0.037	B
Vest4		0.18
MutPred		0.14		Loss of phosphorylation at T573 (P = 0.0276)
MVP		0.85
MPC		1.0
ClinPred		0.22	T
GERP RS		6.0
Varity_R		0.18
gMVP		0.57
Mutation Taster		=43/57	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: rs900079494; hg19: chrX-41419052;