NM_001367721.1:c.1269C>T

Variant names:

• chrX-41586952-G-A
• rs17315800
• NM_001367721.1:c.1269C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001367721.1(CASK):​c.1269C>T​(p.Asn423Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,064,748 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.

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.1269C>T	p.Asn423Asn	synonymous	Exon 14 of 27	NP_001354650.1
	CASK	NM_003688.4		c.1269C>T	p.Asn423Asn	synonymous	Exon 14 of 27	NP_003679.2
	CASK	NM_001410745.1		c.1251C>T	p.Asn417Asn	synonymous	Exon 13 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.1269C>T	p.Asn423Asn	synonymous	Exon 14 of 27	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.1269C>T	p.Asn423Asn	synonymous	Exon 13 of 25	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.1251C>T	p.Asn417Asn	synonymous	Exon 13 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1064748 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 336056

African (AFR) AF: 0.00 AC: 0 AN: 25800

American (AMR) AF: 0.00 AC: 0 AN: 35087

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19125

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29940

South Asian (SAS) AF: 0.00 AC: 0 AN: 53074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39773

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3953

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 813097

Other (OTH) AF: 0.00 AC: 0 AN: 44899

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Najm type Uncertain:1

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.5
DANN	Benign	0.64
PhyloP100		2.5

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: rs17315800; hg19: chrX-41446205; COSMIC: COSV100587773; COSMIC: COSV100587773;